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)
- Exclude, or assign an ACGS/ACMG classification to a variant (for further details see the recording interpretation page)
- Add a comment, and select a transcript and contribution to phenotype for a variant
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 | 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. |
| 2 | 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. |
| 3 | 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. |
| 4 | 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. |
| 5 | Genes | HGNC gene symbol(s) which the variant affects. For further details, please visit the genes section below. |
| 6 | 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. |
| 7 | OMIM associated diseases | Count of associated diseases for the gene in OMIM.For further details, please visit the OMIM section below. |
| 8 | Most severe change | The c. and p. HGVS nomenclature for the transcript with the most severe change for the variant. The flag to the right indicates whether the change is the most severe change (S), or whether it is the change for the MANE Select (M) or MANE Plus Clinical (M+) transcripts. For further details, please visit the most severe change section below. |
| 9 | Most relevant consequences | Predicted consequence types (SO terms) for transcripts that have a consequence matching the most severe consequence for the gene, and any consequences for MANE Select and MANE Plus Clinical transcripts. For further details, please visit the most relevant consequences section below. |
| 10 | Max allele frequency | Maximum allele frequency for the variant across gnomAD and Genomics England internal studies. |
| 11 | 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 |
| 12 | 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 New IB or other existing products, are sent to CVA. |
| 13 | 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 |
| 14 | Segregation, MOI, penetrance | Displays the segregation, mode of inheritance, and penetrance for the variant. 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 |
| 15 | 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. 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) |
| 16 | QC Flag | Indicates whether the variant passed QC filters applied during the analysis. Obtained from the VCF file |
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.
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 | 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. |
| 9 | Variant penetrance | Variant penetrance |
| 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. |
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 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, with the data used for annotation being updated every hour (data is static once the case is ingested into the New IB).
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). 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 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 that is used for annotating variants will be updated at least every quarter.
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 transcript with the most severe change across all transcripts that overlap with the variant. The (S) flag indicates that it is the most severe change. Additional flags (M and/or M+) may also be shown, if the change is associated with a transcript that is a MANE Select or MANE Plus Clinical, respectively.
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)
Most relevant consequences¶
In the grid, we display the consequences (SO terms) for transcripts that have a consequence that matches the most severe consequences for the gene. We also display any consequences for MANE Select and MANE Plus Clinical transcripts.
This column lists the most severe consequence associated with the variant, across all transcripts. This is flagged with an S. In addition, it also lists the consequences of the MANE Select (M) and MANE Plus Clinical (M+), 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 |
| 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 |