Small Variant Details

This page provides more detail about a specific variant. For details on how to use the classification card, and how this is saved in the history, see the recording interpretation page page.

Variant informationGene informationPopulation frequenciesSegregation informationOther databasesPrioritisation results

Variant information

The variant information card contains basic information about the variant.

Key

#	Section	Description
1	Variant coordinates	VCF format of the variant
2	Copy nomenclature button	Copies the variant coordinates in Alamut format
3	External links	Contains links to external databases and resources for the variant (DECIPHER, gnomAD, UCSC, VarSome and SpliceAI).
4	Header	Contains the same details as sections 1, 2, and 3, as well as the type of SNV,which remain visible upon scrolling.

Gene information

The gene information card contains a tab for each gene that the variant is seen in. Clicking on each gene tab provides more information about that gene and its transcripts.

If there are no genes associated with the variant, then No associated genes is displayed in place of all gee information.

Key

#	Section	Description
1	Gene name	Gene name
2	Gene colour	The gene is coloured green when it is green in the most recent PanelApp version, and that panel matches the GMS PanelApp panel applied to the patient (i.e. it is counterpart to the GMS version). Green gene status currently only applies to Tiered variants.
3	Gene ID	Ensembl gene ID

Non-GMS PanelApp panelsOMIM associated diseasesExternal linksTranscript information

Non-GMS PanelApp panels

This section displays the non-GMS PanelApp panels for the gene (including version and a link-out to the PanelApp page for the panel). For each panel, 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, 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 non-GMS PanelApp panels, then None is displayed in place of all data.

PanelApp data is queried, per case, at the point of ingestion, thus it is the latest available at the point in time the patient was loaded into the New IB.

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 will be displayed in a table, and pages of the table can be navigated between using the arrow buttons.

External links

Linkouts to external resources and databases for the gene (OMIM, PubMed, PanelApp, ClinGen).

Transcript information

Table containing details of transcripts for that gene which overlap the variant. A '-' in the table indicates that this data is not available for the transcript. Transcripts are ordered by the following priority:

1. Most severe consequence
2. Mane Select
3. Mane Plus Clinical
4. GENCODE Basic

Any transcripts that do not match the above criteria are displayed unordered.

Key

#	Section	Description
1	Transcript / RefSeq Match	Ensembl transcript ID is provided for each transcript, and RefSeq NM number is provided for MANE transcripts. These provide linkouts to the respective transcript pages. RefSeq transcript IDs are only provided for MANE transcripts, as only these guarantee 100% sequence identity between the respective Ensembl and Refseq transcript IDs. If the transcript is MANE then a flag will be displayed (M for MANE Select and M+ for MANE Plus Clinical). If more than 5 transcripts exist, then these can be navigated through using the arrows at the bottom of the table
2	CDS change	The c. HGVS nomenclature for the CDS change
3	Protein change	The p. HGVS nomenclature for the protein change
4	Consequence	Predicted consequence types (SO terms) for the transcript. N.B. multiple consequences can be associated with the same transcript. If the consequence is the most severe, an S flag will be displayed
5	Protein ID (Ensembl ID)	Ensembl ID for the protein produced by the transcript
6	Entries per page	Number of transcripts to display in the table can be modified using this drop-down
7	Navigation arrows	Navigate through pages of the table using these buttons

Population frequencies

The population frequencies card provides allele frequency details for all available studies for the variant, as annotated by CellBase (Genomics England Annotation Service). A table is displayed per study. This could include: gnomAD mitochondrial (only visible for mitochondrial variants), gnomAD genomes, gnomAD exomes, and Genomics England internal studies. If the variant has a gnomAD allele frequency of 0 for a study subpopulation in gnomAD, then the row for that subpopulation will not be displayed in the table for that study. If the variant has no population data available for a single study, then No entries will be visible in the table for that study. If the variant has no population data available across all studies, then a message No entries for this variant in gnomAD or Genomics England internal database will be visible in place of the individual study data.

Where a variant has an allele frequency of more than 0 and less than 0.0001, this will be displayed as <0.0001. For any allele frequency of >0.0001, the exact value will be displayed.

To find out the versions of population datasets used for annotation, please visit the software and dataset versions section.

Key

#	Section	Description
1	Tooltip	Provides additional information about the section
2	Max allele frequency	Maximum allele frequency across all studies. Click on the tooltip for higher granularity (allele count and allele number)
3	Study	Study which contains the subpopulation with the maximum allele frequency across all studies

gnomAD exomes and genomesgnomAD mitochondrialGEL internal

gnomAD exomes and genomes

These tables display gnomAD population frequency data for the variant, from the exomes and genomes population datasets.

Key

#	Section	Description
1	Study name	Name of the study - gnomAD exomes or gnomAD genomes
2	Population	Data is provided by population within the study. Population is only visible where number of alt alleles > 0
3	Alt allele frequency for the variant	Frequency of the variant within the population dataset
4	Number homozygous genotypes	Number of individuals within the population dataset that are homozygous for the variant
5	Number of alt alleles	Number of times the variant is observed within the population dataset
6	Allele number - total number of alleles	Total count of reference alleles and variant alleles observed in the population dataset for that variant

gnomAD mitochondrial

If the variant is mitochondrial, this table displays gnomAD MT population frequency data for the variant.

Key

#	Section	Description
1	Population	Data is provided by population within the study. Population is only visible where homoplasmic allele count > 0
2	Homoplasmic allele frequency	Proportion of individuals carrying the homoplasmic variant allele within the population dataset
3	Homoplasmic allele count	Number of individuals within the population dataset carrying the mitochondrial variant in a homoplasmic state
4	Allele number - total number of alleles	Total count of reference alleles and variant alleles observed in the population dataset for that variant. N.B. this value is not available for the Genomics England dataset

GEL internal

Genomics England internal population frequency data. Currently the number of alternate alleles and the total number of alleles are not available to display in the New IB. Further details can be found in the rare disease pipeline user guide.

Key

#	Section	Description
1	Population	Data is provided by population within the study
2	Alt allele frequency for the variant	Frequency of the variant within the population dataset

Segregation information

The segregation information card provides information on variant segregation for the proband and relatives.

The table can acommodate up to five individuals. The segregation is currently only available for variants that are included in the Interpreted Genome (Tiers 1,2,3), as this annotation is generated by and comes from the RD pipeline.

Key

#	Section	Description
1	Zygosity	Relationship between the alleles at the locus
2	Proband / Mother / Father etc.	A column per related individual is displayed, up to a maximum of 5
3	Affected status	The affected status of the individual (Affected, Unaffected, or Uncertain)
4	Patient ID	Genomics England patient identifier
5	Sample ID	Genomics England sample identifier
6	Zygosity	Visual representation of the zygosity for the individual. See the Zygosity visualisation section for further details
7	Alt reads	Number of variant-supporting reads for the individual
8	Ref reads	Number of reference-supporting reads for the individual
9	Total reads	Total number of reads for the individual (ref reads + alt reads)

Zygosity visualisation

Zygosity is visualised according to the below criteria. For mitochondrial variants, Dragen 4 uses AF thresholds to determine the plasmy (Heteroplasmic = AF < 0.95, homoplasmic = AF ≥ 0.95).

N.B. As the sample is blood, for mitochondrial variants the plasmy may not be representative of that of the tissue related to the disease

• No call and unknown represent missing data where no genotype is available
• Half missing represents where one allele is observed but the other allele's data is missing

Other databases

The other databases information card displays a table with information about the variant classifications. Currently, only ClinVar classifications are displayed here.

N.B. these annotations are static and added at the time of analysis of the case by the pipeline

ClinVar

Key

#	Section	Description
1	Accession	ClinVar Variation identifier for the variant (uniquely identifies the variant in ClinVar)
2	Review status	ClinVar Level of review supporting the variant classification
3	Submissions	Number of ClinVar submissions contributing to the review status
4	Classification	ClinVar aggregate classification for the variant
5	Interpretation	Total submissions for each classification category, across all ClinVar submissions for the variant (Pathogenic, Likely Pathogenic, Uncertain significance, Likely benign, Benign). IF the count for any category is 0 then that classification category is not displayed.
6	Last submission	Latest submission for the variant at the time of analysis by the pipeline

Prioritisation results

The prioritisation results card displays the prioritisation outcomes for the variant, both Genomics England Tiering and Exomiser.

Tiering

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

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	Tooltip	Provides additional information about the section
2	Tiering	Button for the Genomics England Rare Disease Tiering tab
3	Highest Tier	The highest Tier assigned to the variant by Genomics England Rare Disease Tiering
4	Clinical indication	The clinical indication for the proband
5	Tier	Tier assigned by Genomics England Rare Disease Tiering
6	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.
7	Gene	Gene for the Genomics England Rare Disease Tiering result
8	Gene colour	The gene is coloured green when it is green in the most recent PanelApp version, and that panel matches the GMS PanelApp panel applied to the patient (i.e. it is counterpart to the GMS version).
9	Variant segregation	The segregation that the variant fits with and that led to this Tiering outcome - it may be any of these terms
10	Variant MOI	The mode of inheritance that the variant fits with and that led to this Tiering outcome - it may be any of these terms.
11	Variant penetrance	Variant penetrance
12	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
13	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 the GEL allele frequency and max allele frequency considered by Exomiser, are displayed at the top of the card. Below this, a table displays all Exomiser ranks and corresponding scores for the variant, in a tabular format. Values are displayed up to 4 decimal places.

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 Exomiser rank or score for a variant (e.g. a variant wasn't considered by Exomiser), there will be no data visible, only the text: This variant was not prioritised by the Exomiser algorithm.

Key

#	Section	Description
1	Highest rank	Highest Exomiser rank for the variant
2	GEL allele frequency	Maximum Genomics England allele frequency for the variant
3	Max allele frequency	Maximum allele frequency for the variant, as considered by Exomiser, which includes various AF cohorts. See details here.
4	Rank	The rank of the variant in comparison to the maximum Exomiser score for each SNV in the case. Rank = 1 represents the most likely causative candidate
5	Score	Overall Exomiser score. For further details on how this is calculated visit the Rare Disease Genome Analysis Guide
6	Gene phenotype score	The phenotypic similarity of patient phenotypes, on a scale of 0-1. Higher values indicate higher relevance, phenotype-wise. For further details on how this is calculated visit the Rare Disease Genome Analysis Guide
7	Variant score	The rarity and pathogenicity of the variant on a scale of 0-1. Higher values indicate higher relevance, pathogenicity-wise. For further details on how this is calculated visit the Rare Disease Genome Analysis Guide
8	Gene variant score	Gene-level variant score. The highest score across all variants within the gene. For further details on how this is calculated visit the Rare Disease Genome Analysis Guide
9	Gene	Gene(/s) associated with the Exomiser finding
10	Variant MOI	Mode of inheritance being considered by Exomiser
11	Variant penetrance	Penetrance being considered by Exomiser

Abbreviations

Abbreviation	Definition
ACGS	Association for Clinical Genomic Science
ACMG	American College of Medical Genetics and Genomics
CDS	Coding DNA Sequence
CNV	Copy Number Variant
CVA	Clinical Variant Ark
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
IP	Interpretation Portal
NGIS	National Genomics Informatics System
PID	Patient Identifiable Data
QC	Quality Control
SO	Sequence Ontology
SNV	Single Nucleotide Variant
SV	Structural Variant
TOMS	Test Order Management Service
UAT	User Acceptance Testing
VCF	Variant Call Format File
WGS	Whole Genome Sequencing