Variant annotations¶

Cases are processed via the bioinformatics pipeline and annotations are added by CellBase. Once a case arrives to the New IB, additional annotations are added from resources that are currently unavailable in CellBase.

Annotation	Description	Source	Static / Live
Tiering results	Tier, segregation, mode of inheritance, penetrance	Genomics England Rare Disease Tiering, Genomics England Rare Disease pipeline	Static (Annotated by the Genomics England Rare Disease Tiering pipeline)
GMS PanelApp panels	Panel name and version, gene and green status	GMS PanelApp	Static (Annotated by the Genomics England Rare Disease Tiering pipeline)
Segregation, MOI, penetrance	Segregation, MOI and penetrance groupings from the Tiering prioritisation results (previously known as Report Events)	Genomics England Rare Disease Tiering, Genomics England Rare Disease pipeline	Static (Annotated by the Genomics England Rare Disease Tiering pipeline)
Exomiser results	Exomiser prioritisation results, with associated scores, ranks and allele frequencies	Genomics England Rare Disease Tiering, Genomics England Rare Disease pipeline	Static (annotated by Exomiser, as part of the Genomics England Rare Disease pipeline)
Gene, transcript and protein annotations (ID, flags, consequences)	Gene, transcript and associated annotations	CellBase	Static (Limited by CellBase version. Annotated at case ingestion)
PanelApp panels	Panel name and version, gene status, gene mode of inheritance	PanelApp	Static (Annotated at case ingestion. The underlying dataset used for annotation is updated with the most recent PanelApp data every hour).
OMIM	Associated diseases and gene-phenotype mode of inheritance	CellBase	Static (Annotated at the point of case ingestion. The underlying data used for annotation is updated with the most recent OMIM data with every New IB release).
REVEL	An in-silico prediction score used to estimate the likelihood that a missense variant is disease-causing. Scores range from 0 to 1, with higher scores indicating a greater predicted likelihood that the variant is pathogenic.	CellBase	Static (Limited by CellBase version. Annotated at case ingestion)
gnomAD population frequency	Population germline allele frequency database	CellBase	Static (Limited by CellBase version. Annotated at case ingestion)
GEL population frequency	Internal germline allele frequency database	Genomics England dataset	Static (Annotated at the point of case ingestion. Also used within the Genomics England Rare Disease pipeline)
CVA	CVA entr(y/ies) for the variant, with classification and count	CVA	Live
ClinVar submissions	ClinVar Germline Database - accession, review status, submissions, classification, interpretation, latest submission	CellBase	Static (Limited by CellBase version. Annotated at case ingestion)
Zygosity	Variant zygosity	Variant genotype, from the variant VCF file (generated by the Genomics England Rare Disease pipeline)	Static (Annotated at case ingestion, using the VCF file)
Ref / alt / total reads	Reference / alternative / total read counts	Variant VCF file (Generated by the Genomics England Rare Disease Pipeline)	Static (Annotated at case ingestion, using the VCF file)
DQ score	Posterior probability scores calculated from the possible genotypes within the family. Indicate the level of confidence that a variant represents a genuine de novo event. Higher scores indicate greater confidence in the supporting evidence.	Variant VCF file (Generated by the Genomics England Rare Disease Pipeline)	Static (Annotated at case ingestion, using the VCF file)
QC filter data	Indicates whether the variant passed QC filters applied during the analysis	Variant VCF file (Generated by the Genomics England Rare Disease Pipeline)	Static (Annotated at case ingestion, using the VCF file)

Data sources¶

To read more about each data source used within the product, and where it is used, please click on the below tabs.

GEL pipelineCellBasePanelAppCVAOMIM

GEL Tiering¶

Prioritisation results are the results from the Rare Disease Genomics England Tiering pipeline for the variant and the applied panels. This comprises of various metadata, including Tier, associated gene(s), segregation, mode of inheritance, and penetrance. These are displayed within the app within the Tier overlay, Tier columns in the variant grids, and the SNV details pages.

For further information on GEL Tiering, visit the Tiering section in the Genomics England Rare Disease Pipeline user guide.

GMS PanelApp¶

GMS PanelApp panels (including version, gene and green status), are annotated by the Genomics England Rare Disease Tiering pipeline. These are displayed within the app at locations including the case summary page, and the Tier overlay.

Exomiser¶

Exomiser is a programme that finds potential disease-causing variants from whole-exome or whole-genome sequencing data. All rare disease cases are run through the Exomiser automated variant prioritisation framework. Exomiser results and explainability data are displayed within the app within the Exomiser column in the SNV grid, the accompanying Exomiser overlay, and within the SNV details page.

For further information on Exomiser prioritisation, visit the Exomiser page in the Genomics England Rare Disease Pipeline user guide.

Segregation, MOI, penetrance¶

The segregation, MOI and penetrance groupings displayed within the New IB currently come from the GEL Tiering prioritisation results (previously known as Report Events). In future, it is planned that this data for Exomiser prioritisation results, and also for untiered variants, will be added to the annotations provided.

Zygosity¶

Zygosity is annotated per variant per individual in the case, at the point of case ingestion, using the variant VCF file. The variant VCF file is generated by the Genomics England Rare Disease pipeline.

Ref / alt / total reads¶

Reference / alternative / total read counts are annotated per individual in the case, at the point of case ingestion, using the variant VCF file. The variant VCF file is generated by the Genomics England Rare Disease pipeline.

DQ score¶

DQ scores are posterior probability scores calculated from the possible genotypes within the family and indicate the level of confidence that a variant represents a genuine de novo event. Higher scores indicate greater confidence in the supporting evidence.

DQ scores are only calculated where sufficient family data are available, such as for trios or larger family structures containing the relevant parental samples. They are not available for singleton cases. Scores may also be unavailable for cases ingested before DQ annotations were introduced, or for individual variants where no score was recorded. In these cases a warning symbol will be displayed in place of the scores, with an explanation displayed on hover.

DQ scores are displayed in the SNV grid, and where the score for a variant exceeds the pipeline thresholds (see below), a de novo label is displayed.

SNVs: ≥0.0013
Indels: ≥0.02

QC filter data¶

This indicates whether the variant passed QC filters applied during the analysis, and is annotated by the Genomics England Rare Disease Pipeline, where it is stored in the VCF file.

Gene, transcript and protein annotations (Ensembl / RefSeq)¶

Ensembl is a genome browser that provides gene annotations.

CellBase annotates each variant with gene, transcript and associated annotations from Ensembl
The New IB displays these annotations in the variant grid and variant details page
The database version of Ensembl used by CellBase may not always be the most recent. Please see the latest version of the Rare Disease Genome Analysis guide for further details.

gnomAD population frequencies¶

The Genome Aggregation Database (gnomAD) is a population frequency database of large-scale sequencing projects from healthy cohorts.

CellBase annotates whether a variant is present in gnomAD (exomes, genomes and mitochondrial datasets)
The New IB displays the total population germline allele frequency as well as the subpopulations
The database version of gnomAD used by CellBase is displayed in the New IB and may not always be the most recent.

GEL population frequencies¶

SNV and CNV variants are annotated with the GEL internal allele frequency dataset upon case ingestion. This is a GEL internal population frequency dataset. N.B this dataset is also used within the Genomics England Rare Disease pipeline; for further details, please see the Rare Disease Genome Analysis Guide.

ClinVar¶

ClinVar is a public database of variant and phenotype relationships alongside supporting evidence and clinical interpretation histories.

CellBase annotates whether a variant is present in Clinvar.
The New IB displays the ClinVar ID, interpretation, review status and number of entries alongside a link to the ClinVar record in the variant grid and variant details page for germline variants.
The database version of ClinVar used by CellBase is displayed in the New IB and may not always be the most recent. Please see the latest version of the Rare Disease Genome Analysis guide and CellBase for further details.

REVEL¶

REVEL (Rare Exome Variant Ensemble Learner) is an in-silico prediction score used to estimate the likelihood that a missense variant is disease-causing. Scores range from 0 to 1, with higher scores indicating a greater predicted likelihood that the variant is pathogenic.

REVEL scores were calculated for missense variants using GENCODE v19 transcripts on the hg19 assembly and subsequently lifted over to GRCh38. Scores are matched to each transcript using the variant and amino acid change, rather than the transcript identifier.

Because REVEL scores were calculated using legacy transcript models, scores may be unavailable where changes to the genome assembly, transcript structure, or amino acid annotation have created differences from the original REVEL source data.

REVEL is made available under the Open Database License (ODbL).

CellBase annotates missense variants against each transcript using the variant and amino acid change, rather than using the transcript identifier
Transcript-level scores are displayed in the transcript tables in the SNV details page and the gene overlay in the SNV grid
Highest score for the gene where a missense consequence is displayed in the SNV grid=== "PanelApp"

PanelApp¶

The GEL PanelApp knowledgebase allows virtual gene panels related to human disorders to be created, stored and queried and is used as the platform for achieving consensus on gene panels in the NHS Genomic Medicine Service (GMS).

The Ensembl gene ID of each variant is used to match the variant to Panels in PanelApp
The Panels (and superpanels) in which the affected gene is present are then shown on the variant grids and variant details page

CVA¶

The Clinical Variant Ark (CVA) is the knowledge base built from NHS Clinical Scientist interpretations of rare disease patients in the 100K Genomes Project and NHS Genomic Medicine Service. For further information, visit the CVA user guide.

OMIM¶

OMIM data is used to annotate the variants with associated diseases and gene phenotype mode of inheritance. The data is static, and is annotated at the point of ingestion, with the underlying data used for annotation being updated with each New IB release.

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