Small Variant Grid

This page provides the ability to:

• Sort variants by Tier or Exomiser score
• Review the germline small variants identified by the Genomics England Rare Disease Pipeline (DRAGEN)
• Review additional annotations and linkouts to external resources for each variant (see SNV grid guide below for further details)
• Assign an ACGS/ACMG classification to a variant, including selecting a transcript, contribution to phenotype, and adding a comment (see the recording interpretation page)
• Exclude a variant, with reasoning and comment (see the recording interpretation page)
• See a history log of interpretation actions

N.B The New IB supports cases with SNVs that were processed since release 4.0, CNVs that were processed since release 4.2, and cases with Tiered STRs that were processed since release 4.3. Any cases that do not fit these criteria are not supported by the product, therefore it will not be possible to analyse them in the New IB, and alternative existing systems should be utilised to analyse the case.

SNV grid guide

The order of columns in the SNV grid can be changed using the column headers. This will reset to default upon navigating away from the page or on page refresh. 20 variants are shown by default, and more are loaded dynamically when scrolling to the bottom of the page.

Please use the below key in conjunction with the below sections to learn more about the columns in the variant grid.

Key

#	Section	Description
1	Variant count	Summarises the number of variants currently displayed in the grid, and the total number of variants matching the selected filters.
2	Filter status	Denotes whether filters have been applied or there were no filters applied at all. GEL default filter applied indicates that the default set of filters is active, Custom filters applied indicates that an alternative combination of filters is active, No filters applied denotes that no filters are active.
3	Filters	Filter drop-downs can be used to apply various filters to the variant list: VCF filter, Tier, Segregation, Penetrance, Exomiser. GEL default filters are automatically applied. See the Filters section below below for further details.
4	Actions	A Classify button which can be clicked to open the classification drawer, and changes to display the classification of the variant once it has been assigned (for further details see the recording interpretation page). Once the classification is selected for the variant, it is displayed in place of the Classify button. A Details button which navigates to the variant details page for the variant.
5	Tier	This can be Tier 1, Tier 2, Tier 3, or "-" for untiered variants or variants that do not fall within a gene. For further details, please visit the Tier section below.
6	Exomiser	The highest Exomiser rank and corresponding score for the variant are displayed in the column. For further details, please visit the Exomiser section below.
7	Variant	The VCF format of the variants, with a button that can be used to link-out to IGV (for read depth investigation). There is also a button that opens a menu containing further links to external databases and resources (DECIPHER, gnomAD, UCSC, VarSome and SpliceAI) for the variant, and a button to copy the variant coordinates in Alamut format.
8	Genes	HGNC gene symbol(s) which the variant affects. For further details, please visit the genes section below.
9	Gene colour	Genes in Tiered variants are coloured green according to their PanelApp green gene status. For further details, please visit the genes section below.
10	OMIM associated diseases	Count of associated diseases for the gene in OMIM. For further details, please visit the OMIM section below.
11	Most severe change	The c. and p. HGVS nomenclature for the transcripts for the gene visible in the row that are any of: 1. The most severe change across the annotated transcripts for that gene (indicated by the (S) flag), 2. A MANE Select or MANE Plus Clinical transcript (indicated by (M and/or M+)). For further details, please visit the most severe change section below.
12	Most relevant consequences	Predicted consequence types (SO terms) for the gene that is visible in the row, which are the most severe across all annotated transcripts for that gene, plus we also display any consequences for MANE Select and MANE Plus Clinical transcripts annotated for that gene. For further details, please visit the most relevant consequences section below.
13	Max allele frequency	Maximum allele frequency for the variant across gnomAD and Genomics England internal studies.
14	gnomAD counts (Alt/Total alleles | Homozygotes)	Displays, for the variant, across gnomAD studies within which we see the variant, the total number of alt alleles (number of times the variant is observed), the total number of alleles, and the number of homozygous genotypes (number of individuals that are homozygous for the variant). It is currently not possible to display this data for mitochondrial variants, therefore population frequency data for these variants must be reviewed in the variant details page. N.B. the column displays gnomAD totals only as the number of alt alleles is not available for the Genomics England dataset.
15	CVA	Displays any CVA classifications for the variant. The number of cases the variant has been seen in is displayed, with a link-out to the CVA page for the variant, plus the number of previous classifications per classification type, or Unclassified if there have been no previous classifications. This data is live when viewing the case. If the variant is not in CVA, then a '-' is visible. If there is an error with loading the data then a red i icon will be displayed. All cases, regardless of whether they were analysed in the New IB or other existing products, are sent to CVA.
16	ClinVar	ClinVar accession number, review status and link-out to the ClinVar entry are displayed here. If there is more than one accession number for the variant, the accession with the most submissions is displayed first (and if equal then the most pathogenic will be displayed first). Further entries will be denoted by the +X entries indicator, which can be clicked to view a ClinVar overlay.
17	Segregation, MOI, penetrance	Displays the segregation, mode of inheritance, and penetrance groupings for Tiering events for the variant (N.B. groupings from Exomiser are not visible, nor are they visible for untiered variants). If there are multiple groups of these, they will be displayed one above the other (CP = complete penetrance, IP = incomplete penetrance). If there are 3 or more groups, only the first is displayed and a link is provided displaying the number of additional groups. When the link is clicked, the Tier overlay opens.
18	Zygosity (Proband / Mother / Father etc.)	A column for the proband and one per family member, containing the zygosity symbols, and ref/alt read split information. Affected status is indicated for each individual in the column header. More details can be found in the segregation card on the Variant Details page for the variant. On hover over the zygosity symbols, the affected status of the individual is displayed (X Affected, X Unaffected or X Uncertain).
19	QC filter	Indicates whether the variant passed QC filters applied during the analysis. Obtained from the VCF file.

SortingFiltersTierExomiserGenesOMIMMost severe changeMost relevant consequencesClinVar overlay

Sorting

By default, all variants are sorted by Tier ascending and by variant coordinates. Variants can be sorted by Tier, Exomiser rank or Exomiser score ascending or descending by using the arrow icon or menu in the column headers.

Please note, sorting by Tier and Exomiser columns are independent of one another - if you apply a sort on one after sorting on the other, a combination sort will not apply - the sort will simply be overruled.

Filters

Filters can be used to narrow the variants displayed in the variant grid to variants of interest with specific selected attributes. The filters are located above the grid column headers.

The number of variants returned by the filters, and number of variants currently visible in the grid, is highlighted by the counts above the applied filters.

For further details on various aspects of the filtering behaviour, please view the tabs below.

GEL defaultsRemove filtersVCF filterTier filterSegregation filterPenetrance filterExomiser filterFilter combinations

GEL default filters

A pre-set combination of filters, GEL default filters, are applied to the SNV grid by default in order to restrict the visible variants to those that are of interest for interpretation, and reduce noise. The set of default filters are as follows:

• VCF filter: PASS
• Tier: Tier 1, Tier 2

When GEL default filters are active, GEL default filter applied is visible at the top of the grid. Additional filters can then be selected, or one or multiple of the GEL default filters deselected. Custom filters applied will then be visible at the top of the grid.

If the GEL default filters or custom filters return no variants, this is clearly indicated by a message within the grid.

Removing filters

Filters can be removed easily by:

• Deselecting the filter selection or clicking clear within the multi-select drop-downs
• Clearing the text box manually, or clicking the cross, within the Exomiser drop-down
• Clicking the Reset button if custom filters have been applied, which reverts the filters back to the GEL default filters

If all filters have been removed, No filters applied will be visible at the top of the grid.

VCF filter

Variants can be filtered based upon whether they passed QC filters applied during the analysis. This is an annotation produced by the Genomics England Rare Disease Pipeline which originates from the VCF file. There are 2 selection options (see below). If both are selected, variants will be displayed that match either selection.

• VCF filter PASS
• VCF filter non-PASS

Tier filter

Variants can be filtered based on their Tier as assigned by the Genomics England Rare Disease Pipeline. There are 4 selection options (see below). This filter works at the Tiering event level, so if a variant has any Tiering events that match that Tier, then the variant will be displayed within the filter results. If multiple are selected, variants will be displayed that match any selection. N.B. If Tier 3 is selected, and the variant has a Tier 3 Tiering event but also has a higher Tiering event (for example Tier 1), then that variant will still be displayed within the grid.

• Tier 1
• Tier 2
• Tier 3
• Untiered

Segregation filter

Variants can be filtered based on the segregation for their Tiering event(/s) as assigned by the Genomics England Rare Disease Pipeline. There are 11 selection options (see below). This filter works at the Tiering event level, so if a variant has any Tiering events that match that segregation, then the variant will be displayed within the filter results. If multiple are selected, variants will be displayed that match any selection. N.B. this filter is Tiering event specific - when applied, variants with no Tier report event(/s) will be filtered out by default

• De novo
• Dominant
• Dominant (PI)
• Dominant (MI)
• Simple recessive
• Compound het
• X-linked monoallelic
• X-linked simple recessive
• X-linked compound het
• Mitochondrial
• Uniparental isodisomy

Penetrance filter

Variants can be filtered based on the penetrance mode for their Tiering event(/s) as assigned by the Genomics England Rare Disease Pipeline. There are 2 selection options (see below). This filter works at the Tiering event level, so if a variant has any Tiering events that match that segregation, then the variant will be displayed within the filter results. If multiple are selected, variants will be displayed that match any selection. N.B. this filter is Tiering event specific - when applied, variants with no Tier report event(/s) will be filtered out by default

• Complete
• Incomplete

Exomiser filter

Variants can be filtered based on their Exomiser report event ranks and scores. There are 2 selection options (see below). This filter works at the Exomiser report event level. If one input is applied, any variants with Exomiser report event(/s) that match that condition are returned. If multiple are applied, variants that match both conditions within the same report event(/s) are returned.

#	Filter	Description
1	Exomiser rank ≤ X	Minimum input value is 1, and there is no maximum value - i.e. any value can be input that is 1 or above. If an input doesn't match these criteria, an error message will be displayed: Value must be greater than X
2	Exomiser score ≥ Y	Minimum input value is 0, and maximum is 1. Inputs can have decimals. If an input doesn't match these criteria, an error message will be displayed: Value must be between X and Y

Filter combinations

Filters can be applied in combinations to further narrow down the number of variants displayed within the grid. For example, if the VCF pass filter was applied at the same time as the Tier filter, the variant would need to meet both criteria to be displayed within the grid in the filter results. There are several notable caveats to this:

#	Filter combination	Behaviour
1	Tier + penetrance (or Tier + segregation)	When Tier filter(/s) and penetrance filter(/s) are selected, variants are returned that have a Tier and penetrance value matching the user selection, which exist within the same Tier report event. The same behaviour is true for Tier + segregation.
2	Tier + penetrance + segregation	When Tier filter(/s), penetrance filter(/s), segregation filter(/s) are selected, variants are returned that have a Tier value, penetrance value, and segregation value that match the user selection, which all exist within the same Tier report event.
3	Exomiser + penetrance (or Exomiser + segregation)	When Exomiser filter(/s) and penetrance filter(/s) are selected, variants are returned that have meet those Exomiser filter criteria within the same Exomiser report event, plus have a selected penetrance value within any Tier report event. The same behaviour is true for Exomiser + segregation.
4	Exomiser + penetrance + segregation	When Exomiser filter(/s), penetrance filter(/s), and segregation filter(/s) are selected, variants are returned that meet those Exomiser filter criteria within the same Exomiser report event, plus have that penetrance value and selected penetrance value(/s) and segregation value(/s) within the same Tier report event.

Tier

This can be Tier 1, Tier 2, Tier 3, or "-" for untiered variants or variants that do not fall within a gene. When clicking on the tooltip next to the Tier, the Tier overlay opens.

For details on how to sort by Tier, please visit the sorting section.

Tier overlay

The Tier overlay displays details about the Genomics England Tiering outcome for the variant.

The highest Tier assigned to the variant and the clinical indication for the proband are displayed at the top of the overlay.

Below this we see all prioritisation results (previously known as Report Events) for the variant displayed in a table; the gene, panel, and the variant segregation, inheritance and penetrance considered by Tiering as part of the finding are displayed per prioritisation result.

Key

#	Section	Description
1	Highest Tier	The highest Tier assigned to the variant by Genomics England Rare Disease Tiering.
2	Clinical indication	The clinical indication for the proband.
3	Tier	Tier assigned by Genomics England Rare Disease Tiering. These are sorted in order: Tier 1, Tier 2, Tier 3. The chevron in the column header can be used to toggle the sort between ascending and descending.
4	Source	The source of the Tier assigned to the variant by Genomics England Rare Disease Tiering. This can be either: Standard Tiering, KPVP (ClinVar), KPVP (CVA), Inclusion list. See the Tiering algorithm page in the Rare Disease Genome Analysis Guide for further details.
5	Gene	Gene for the Genomics England Rare Disease Tiering result.
6	Gene colour	The gene pill is coloured green when the gene is green in at least one PanelApp panel (/superpanel) of the most recent version at the time of case ingestion, where that panel is also a panel that has been applied to the case.
7	Variant segregation	The segregation that the variant fits with and that led to this Tiering outcome - it may be any of these terms.
8	MOI consistent with	The mode of inheritance that the variant fits with and that led to this Tiering outcome - it may be any of these terms.
9	Variant penetrance	Penetrance mode under which the variant was tiered. For further details, please visit the penetrance modes page in the Genomics England Rare Disease Genome Analysis Guide.
10	GMS panel name	Name of the GMS panel applied to the patient that is associated with the Genomics England Rare Disease Tiering result, with a link to the GMS signed off PanelApp panel.
11	Links to GEL Rare Disease Genome Analysis Guide	Links to the relevant pages in the Genomics England Rare Disease Genome Analysis Guide.

Exomiser

The highest Exomiser rank and corresponding score for the variant are displayed in the Exomiser column (as the variant may have multiple Exomiser ranks and scores due to e.g. consistency with more than one mode of inheritance, or variant overlapping multiple genes). These are determined by the Exomiser pipeline, based on the HPO terms selected for the case. Further details on the Genomics England implementation of Exomiser can be found in the Rare Disease Genome Analysis Guide.

In the case where there is no Exomsier rank or score for a variant (e.g. a variant wasn't considered by Exomiser), a '-' will be visible. Values are displayed up to 4 decimal places.

Clicking the i icon will open the Exomiser overlay, where any further ranks or scores will be visible, along with additional information considered by Exomiser as part of the scoring (e.g. variant MOI and penetrance).

Exomiser overlay

The Exomiser overlay displays all Exomiser ranks and corresponding scores for the variant, in a tabular format. For each row, the drop-down can be clicked to reveal details on the patient phenotypes that were / were not matched to terms in Exomiser's disease models. Please note, the matched terms themselves and their sources are not displayed in this overlay, but are visible in the variant details page.

Key

#	Section	Description
1	Consequence	Variant consequence.
2	HGVS	Variant HGVS.
3	Highest rank	Highest Exomiser rank for the variant.
4	GEL allele frequency	Maximum Genomics England allele frequency for the variant.
5	Max allele frequency	Maximum allele frequency for the variant, as considered by Exomiser, which includes various AF cohorts. See details here.
6	Rank	The rank of the variant. This is decided by comparing the maximum Score for each SNV in the case. Rank = 1 represents the most likely causative candidate.
7	Score	The combined score integrating variant pathogenicity (Variant score), gene-phenotype similarity (Gene-phenotype score), and inheritance model to prioritize likely causal variants. This score is used to determine the Exomiser Rank. For further details on how this is calculated visit the Rare Disease Genome Analysis Guide.
8	Gene-phenotype score	The similarity score between the patient’s HPO terms and the known phenotypes of the gene/disease (scale of 0-1). This score is determined by comparison (using a semantic similarity algorithm) of the patient's HPO terms to these HPO terms to the HPO terms describing the typical features of diseases caused by the gene which the variant affects. Higher values indicate higher relevance, phenotype-wise. For further details on how this is calculated visit the Rare Disease Genome Analysis Guide.
9	Variant score	The pathogenicity score of a single variant, based on functional impact, conservation, population frequency, and in silico predictions (on a scale of 0-1). Higher values indicate higher relevance, pathogenicity-wise. This score is combined with Gene-phenotype score to produce the Score used to rank the variants. For further details on how this is calculated visit the Rare Disease Genome Analysis Guide.
10	Gene variant score	The highest pathogenicity score among all variants in a gene, reflecting the predicted impact of the most damaging variant (this score does not incorporate phenotype). For further details on how this is calculated visit the Rare Disease Genome Analysis Guide.
11	Gene	Gene(/s) associated with the Exomiser finding.
12	Variant MOI	Mode of inheritance being considered by Exomiser.
13	Variant penetrance	Penetrance being considered by Exomiser.
14	Patient phenotypes	Phenotypes present in the proband.
15	Matched phenotype by Exomiser	The patient's HPO terms that semantically match known HPO terms for the gene. These matches are used to calculate the Gene-phenotype score, which is combined with the Variant score to produce the overall Score used for ranking.
16	Link to GEL Rare Disease Genome Analysis Guide	Link to the relevant page in the Genomics England Rare Disease Genome Analysis Guide.

Genes

HGNC gene symbol(s) which the variant affects; affected genes in the highest Tier are displayed in the grid. Additional genes at lower Tiers are indicated with a +n icon, with n being the number of genes. This also applies to untiered variants, where all genes will be shown. If there are multiple genes at the highest Tier, these are displayed on separate lines within the row, in no particular order.

Clicking on the gene, or +n in the Genes column opens the gene overlay.

Gene colour

The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion.

The +n pill in the Genes column is also coloured green if this same logic applies to any one(/s) of those lower Tiered genes.

Gene overlay

The gene overlay which displays relevant information for the gene.

This includes Ensembl IDs for the gene and transcripts, PanelApp panels (including superpanels) the gene is present in, OMIM associated diseases for the gene, the c. HGVS nomenclature for the CDS change, the p. HGVS nomenclature for the protein change, and links to external resources for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER). All variants are annotated with PanelApp panels and superpanels upon case ingestion, with the underlying dataset used for annotation updated with the most recent PanelApp data every hour (data is static once the case is ingested into the New IB). For further details, see the annotations page.

The gene names can be seen along the top of the overlay; a variant can be associated with more than one gene. Gene names are clickable, with each page displaying the relevant information for that gene.

Key

#	Section	Description
1	Gene name / header	The gene names can be seen along the top of the overlay; a variant can be associated with more than one gene. These are clickable, with each tab displaying the relevant information for that gene.
2	Gene colour	The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion.
3	Gene ID	Ensembl gene ID.
4	Links	Linkouts to external resources and databases for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER).
5	PanelApp panels	This section displays the PanelApp panels for the gene (including version and a link-out to the PanelApp page for the panel). If the panel is present in any superpanels, these are listed within the row under a Superpanels header. For each panel (and superpanels), we see the gene rating (green, amber, red), and PanelApp's MOI for the gene. If there is no MOI recorded in PanelApp, then this will be displayed as Unknown. If the gene has been removed from the panel in the most recent version at the time of case ingestion, then a '-' is displayed in the Gene status column, and the Gene MOI will be displayed as Unknown. If the gene is present in no PanelApp panels, then None is displayed in place of all data.
6	OMIM associated diseases	Displays any diseases associated with the gene in OMIM, as well as the gene-phenotype mode of inheritance, and a link-out to the OMIM page for each disease. Where there is more than 1 associated disease the data is displayed in a table, and pages of the table can be navigated between using the arrow buttons.
7	Transcript information	See the Gene information section on the SNV details page for further details on the transcript table.

OMIM associated diseases

There is a count of associated diseases in OMIM for each gene visible in the row for the variant.

Clicking the i icon opens the OMIM overlay for that specific gene.

OMIM data is annotated at the point of case ingestion, with the underlying data used for annotation being updated with each New IB release. For further details, see the annotations page.

OMIM overlay

The OMIM overlay displays each disease associated with that specific gene in OMIM, the gene-phenotype mode of inheritance, and a link-out to the OMIM page for each disease. If there is no mode of inheritance in OMIM for an associated disease then Unknown will be visible. The pages of the table can be navigated between using the arrow buttons. The associated diseases are ordered with those associated with a green gene coming first, and then ordered alphabetically by associated disease name.

Most severe change

Contains the c. and p. HGVS nomenclature for the transcripts for the gene visible in the row that are any of: - The most severe change across the annotated transcripts for that gene (indicated by the (S) flag) - A MANE Select or MANE Plus Clinical transcript (indicated by (M and/or M+))

If multiple transcripts have the most severe consequence, then the change displayed in the grid is selected based on the following priority order:

• Has the most severe consequence
• Is a MANE Select transcript
• Is a MANE Plus Clinical transcript
• Is the basic transcript (Ensembl GENCODE)

The most severe change is decided by the below priority order:

Consequence priority order

Below is a list of all SO terms annotated by CellBase.

1. copy_number_change
2. transcript_ablation
3. structural_variant
4. splice_acceptor_variant
5. splice_donor_variant
6. stop_gained
7. frameshift_variant
8. stop_lost
9. terminator_codon_variant / start_lost
10. initiator_codon_variant
11. transcript_amplification
12. inframe_insertion
13. inframe_deletion
14. inframe_variant
15. missense_variant
16. splice_region_variant
17. incomplete_terminal_codon_variant
18. stop_retained_variant
19. start_retained_variant
20. synonymous_variant
21. coding_sequence_variant
22. mature_miRNA_variant
23. 5_prime_UTR_variant
24. 3_prime_UTR_variant
25. non_coding_transcript_exon_variant
26. intron_variant
27. NMD_transcript_variant
28. non_coding_transcript_variant
29. 2KB_upstream_variant
30. upstream_gene_variant
31. 2KB_downstream_variant
32. downstream_gene_variant
33. TFBS_ablation
34. TFBS_amplification
35. TF_binding_site_variant
36. regulatory_region_ablation
37. regulatory_region_amplification
38. regulatory_region_variant
39. feature_elongation
40. feature_truncation
41. feature_variant
42. intergenic_variant

Most relevant consequences

In the grid, we display the predicted consequences (SO terms) for the gene that is visible in the row, that are the most severe across all annotated transcripts for the gene. This is flagged with an S. We also display any consequences for MANE Select (M) and MANE Plus Clinical (M+) transcripts annotated for that gene, when these exist. N.B. multiple consequences can be associated with the same transcript.

Sequence Ontology (SO) terms

Below is a list of all SO terms annotated by CellBase.

• 2KB downstream variant
• 2KB upstream variant
• 3' UTR variant
• 5' UTR variant
• NMD transcript variant
• Coding sequence variant
• Feature truncation
• Frameshift variant
• Incomplete terminal codon variant
• In-frame deletion
• In-frame insertion
• In-frame variant
• Initiator codon variant
• Intron variant
• Mature miRNA variant
• Non-coding transcript exon variant
• Non-coding transcript variant
• Splice acceptor variant
• Splice donor variant
• Splice region variant
• Start lost
• Start retained variant
• Stop gained
• Stop lost
• Stop retained variant
• Structural variant
• Synonymous variant
• Terminator codon variant
• Transcript ablation
• Transcript amplification
• Missense variant
• Downstream gene variant
• Upstream gene variant

ClinVar overlay

Clicking on the +X entries indicator when there is more than one ClinVar accession number for a variant will open the ClinVar overlay, displaying more detailed information for each accession number. Visit the Other databases section in the variant details page for further details on this table.

Abbreviations

Abbreviation	Definition
ACGS	Association for Clinical Genomic Science
ACMG	American College of Medical Genetics and Genomics
CDS	Coding DNA Sequence
CIP-API	Genomics England Clinical Interpretation API
CNV	Copy Number Variant
CVA	Clinical Variant Ark
EQ	Exit Questionnaire
New IB	New Interpretation Browser
GEL	Genomics England
GMS	Genomic Medicine Service
GLH	Genomic Laboratory Hub
HGVS	Human Genome Variation Society
HTML	Hyper Text Markup Language
HSCN	Health and Social Care Network (N3)
IGV	Integrative Genomics Viewer
IB	Interpretation Browser
IP	Interpretation Portal
NGIS	National Genomics Informatics System
PID	Patient Identifiable Data
QC	Quality Control
SoF	Summary of Findings
SO	Sequence Ontology
SNV	Single Nucleotide Variant
SV	Structural Variant
TOMS	Test Order Management System
UAT	User Acceptance Testing
VCF	Variant Call Format File
VILs	Variant Interpretation Logs
WGS	Whole Genome Sequencing