RD Tiering Browser¶
The Interpretation Browser provides a comprehensive tool for users to:
- Review variants, including:
- Small Variants (e.g., SNVs & Indels)
- Copy Number Variants (CNVs)
- Short Tandem Repeats (STRs)
- Analyze zygosity for each variant in sequenced family members:
- Filled Black Circle: Presence of the variant
- Single Black Circle: Heterozygosity
- Two Black Circles: Homozygosity
- Dash ("-"): Genotype undetermined
- View additional annotations (e.g., allele frequencies, HGVS annotations, in silico predictions) from CellBase.
- Report additional variants from the VCF files associated with the case.
- Add and comment on interpretative comments.
- Download selected tiered variants in a TSV (Tab Separated Values) file.
- Review gene panel coverage.
- Check read-level support for variants using IGV.js.
- Generate a Summary of Findings.
- Complete a reporting outcomes questionnaire.
Upgrade to Cellbase v5
The Portal has been upgraded to Cellbase version 5. This update improves features such as Show Variant Details, ClinVar Classifications, Add Variants from VCF, and Max Allele Frequencies. For details, see here.
Reviewing Variants¶
Access the Interpretation Browser from the Referral Overview Page. You can also "close" GMS Rare Disease referrals without using the DSS.
Reviewing Variants Key
| # | Section | Description |
|---|---|---|
| 1 | Create Summary of Findings | Generate a Summary of Findings with the number of selected variants. |
| 2 | SNV/Indels | Displays SNV and Indel variants prioritized by Interpretation Services. |
| 3 | Short Tandem Repeats | Shows short tandem repeats identified in the case. |
| 4 | Copy Number Variations | Lists copy number variants found in the case. |
| 5 | VCF Files | Lists downloadable VCF files for each family member. |
| 6 | Filters | Filter variants by parameters such as Tier (1,2, or 3), Panel Name, Penetrance, Disorder, Consequence type, Compound heterozygous, and Exomiser score. Users can also add specific gene names to the “Add variants from VCF” field. Options are available to download variants as TSV or select and add other variants from the VCF. |
| 7 | Variant | Shows coordinates and nucleotide change. Use the "copy button" to add details to your clipboard. |
| 8 | Genes | Displays HGNC gene symbol and Ensembl gene ID. |
| 9 | Zygosity & Read Depth | Indicates zygosity with circles: two unfilled for homozygous wild type, one filled and one unfilled for heterozygote, two filled for alternate homozygous, and "-" for undetermined genotype. Read depth, reported by the Tiering Algorithm, is not available for Exomiser-only variants. |
| 10 | Max Allele Frequency | Shows maximum alternate allele frequency from CellBase. |
| 11 | Interpretation Service | Identifies the service that detected the variant. |
| 12 | CVA Classifications | Displays CVA classifications based on variant classifications from reporting outcomes questionnaires of rare disease referrals. |
| 13 | ClinVar Classifications | Displays ClinVar annotations from a snapshot in CellBase. A "?" indicates the variant is not in ClinVar. |
| 14 | Additional Information | Use the ‘+’ sign to view extra information, including HGVS data. |
Shading of Variants
Green-shaded variants are those added from the VCF file or called by Exomiser but not yet validated.
Unified Tiering¶
The Nembus release introduces unified tiering for CNVs, STRs, and small variants, allowing the Interpretation Portal to display how different variant types may impact a gene.
Small Variants¶
- Compound heterozygous small variants are grouped in the "Variant" column and highlighted in gray. Use the 'Filter by Compound Heterozygous SNVs/Indels' to locate these groups. Additionally, these groups are displayed in the Variant Group column when the variant is expanded.
- The Group of Variants tags for small variants combined with CNVs or STRs are highlighted in yellow to distinguish them from small variant-only combinations. Clicking on these will display additional information, including a link to this user guide. These variant groups also appear in the new "Variant Group" column, showing which SNV report events are linked to a specific group. Note that these variant groups won't be displayed when using the 'Filter by Compound Heterozygous SNVs/Indels' filter.
CNVs¶
- Call Level table: When a CNV is combined with another variant type, expand the CNV to see the group in the Variant Group column within the Report Events Table.
- Gene Level table: A new sortable 'Variant Group' column displays 'variantGroup' values when tagged as Compound Heterozygous.
STRs¶
- When an STR is combined with a small variant, the group is visible in the main view. Expanding the STR reveals the "Variant Group" column if tagged as Compound Heterozygous.
External Database Links¶
The Interpretation Browser allows links to DECIPHER, gnomAD v4, UCSC genome browser, OMIM, SpliceAI, and VarSome.
CVA Classifications¶
CVA classifications are dynamically pulled from the CVA database when the page loads, based on reporting outcomes questionnaires. The CVA "lozenge" links to the associated variant page in the CVA Portal.
Variant Interpretation Log Classifications
CVA classifications in the Interpretation Browser do not include those from variant interpretation logs (VILs). They only include classifications added to the Summary of Findings via Congencia or reporting as described here and associated Outcomes Questionnaires.
Known Pathogenic Variant Prioritisation (KPVP)¶
KPVP enhances the Genomics England Tiering algorithm to include known pathogenic variants that might have been previously filtered out. For more information, refer to the Rare Disease Genome Analysis Guide here.
Warning
ClinVar data used by KPVP is periodically updated in CellBase. ClinVar annotations in the Interpretation Browser may not reflect the latest "live" data in ClinVar. Access live ClinVar data via the ClinVar link in the ClinVar classifications column.
Read Depth¶
Read depth is displayed as reported by the Genomics England Tiering algorithm. For homozygous reference variants, read depth appears as '-/-'. Note that read depth may differ from IGV due to filtering by variant calling and tiering.
Missing Read Depth
When no read depth is reported, "N/A" is shown. Refer to IGV for read depth at these positions. Currently, read depth is not reported by Exomiser or for variants added from VCF for 100K referrals.
Copy Variant Details¶
Clicking the "copy button" in the variant column copies the variant details in Alamut format to your clipboard for easy pasting into the Alamut application.
Download Variants¶
Download variants in TSV format. By default, all variants are selected, but you can choose specific ones. VCF files for all family members can be downloaded from the VCF Files tab.
Search for Variants in Genes Outside of the Applied Panel¶
Add variants from genes not included in the original panel by clicking the “Add variants from VCF” button. Enter the HGNC gene symbol and click “Search” to add PASS status variants to the Interpretation Browser for review. Note: Variants must have a PASS status and a phenotype assigned to be added to the Summary of Findings.
Attention
Only PASS status variants can be added to the Interpretation Browser. Non-PASS variants are viewable only in the Congenica DSS
Short Tandem Repeats (STRs)¶
Results of STR tiering can be viewed and STR pile-up graphs downloaded. In addition, STRs can be selected and commented on for inclusion in the case’s Summary of Findings.
STRs are listed in priority order (Tier 1 > Tier 2 > Tier Null) and can be filtered based on the tier assigned.
Grace Update to STR Tiering
- Pre-Grace Release: Only Tier 1 and Tier 2 STRs with associated pile-up plots are displayed.
- Post-Grace Release: Includes Tier Null STRs, which are detected but fall below the normal threshold for repeats (as curated in Panelapp). Tier Null STRs are displayed with their pile-up plots.
For more information on STR tiering, refer to the Rare Disease analysis guide.
STRs Key¶
| # | Section | Description |
|---|---|---|
| 1 | Short Tandem Repeats | Tab displaying the STRs in the case. |
| 2 | Download STRs TSV | Button to download STRs data in TSV format. |
| 3 | Tier Filter | Filter STRs by their assigned tier (1, 2, Null). |
| 4 | STR Box | Details of the STR, including tier, locus, repeat motif, and repeat numbers. |
| 5 | Location | Genomic coordinates for the STR. |
| 6 | Panels | Panels applied to the case. |
| 7 | Zygosity | Number of copies on both alleles. |
| 8 | Pile-Up Graph | Button to download the pile-up graph for the STR. |
| 9 | Report Events | Details of STRs found in the case. |
| 10 | Score | Tier assigned to the STR (Tier 1, Tier 2, or Tier Null). |
| 11 | Genomic Entity | Gene name and ENSG ID where the STR is located. |
| 12 | Mode of Inheritance | Inheritance mode as listed in PanelApp for the gene. |
| 13 | Panel Name | Panel(s) related to the gene in the “Genomic Entity” column. |
| 14 | Panel Version | Version of the applied panel. |
| 15 | Penetrance | Penetrance of the clinical indication. |
| 16 | Clinical Indication | Clinical indication assigned to the patient. |
| 17 | Interpretation Service | Service (e.g., Tiering) that assessed the variant. |
Copy Number Variants (CNVs)¶
Danny Release Update
- Post-Danny Release: High-quality CNV calls (2 kb-10 kb) overlapping genes or regions in the virtual gene panel(s) are included in tiered CNVs. High-quality CNVs not overlapping with genes or panels are included in Tier Null. These CNVs are available in the CNV VCF file, now with the
.enhanced.cnv.vcf.gzextension.
CNV tiering results are shown in two tables: the “CNV Call Level Table” and the “CNV Gene Level Table”.
CNV Call Level Table¶
The Call Level Table lists all CNVs identified in the proband, allowing selection and commenting for inclusion in the Summary of Findings.
CNV Call Level Table Key¶
| # | Section | Description |
|---|---|---|
| 1 | Copy Number Variations | Tab displaying the CNVs in the case (if any). |
| 2 | Download CNVs | Button to download CNVs in TSV format. Users can select specific CNVs by clicking the “+” next to genomic coordinates and checking the box. |
| 3 | Genomic Coordinates | Genomic coordinates of the CNV (linking out to IGV) and DGV. |
| 4 | Cytobands | Cytobands related to the genomic coordinates of the CNV. |
| 5 | CNV Type | Type of CNV: ’LOSS’ or ‘GAIN’. |
| 6 | Copy Number | Number of copies of the CNV in the sample. |
| 7 | Size bp | Size of the CNV in base pairs. |
| 8 | Allele Frequency by Reciprocal Overlap (LOSS only) | Allele frequency of the CNV by overlap between structural variants. |
| 9 | Allele Frequency by Frequency Track (LOSS only) | Allele frequency from the frequency track applied. |
| 10 | Proportion of Patients with CNV by Reciprocal Overlap (GAIN only) | Percentage of patients with this CNV by overlap. |
| 11 | Proportion of Patients with CNV by Frequency Track (GAIN only) | Percentage of patients with this CNV by the frequency track applied. |
| 12 | Number of Protein Coding Genes | Number of protein-coding genes affected by the CNV. |
| 13 | ISCA ID of the Pathogenic Region in the Panel Applied | ISCA ID of the pathogenic region in the applied panel. |
| 14 | Link to ISCA ID in PanelApp | Link to the ISCA ID with pathogenicity details. |
CNV Gene Level Table¶
The Gene Level Table lists genes overlapping CNV calls in the proband.
CNV Gene Level Table Key¶
| # | Section | Description |
|---|---|---|
| 1 | Gene | Gene name and ENSG IDs affected by the CNV. |
| 2 | Genomic Coordinates of the CNV | Genomic coordinates of the CNV. |
| 3 | CNV Type | Type of CNV: ’LOSS’ or ‘GAIN’. |
| 4 | Copy Number | Number of copies in the patient sample. |
| 5 | Size, bp | Size of the CNV in base pairs. |
| 6 | All Panels Containing this Gene | Genes linked to PanelApp, showing which panels include this gene. |
| 7 | Tiered | Tier of the CNV (TIERA or Null). |
| 8 | DGV | Link to DGV for this CNV. |
Report Events¶
Variants (SNVs, Indels, CNVs, and STRs) in the Interpretation Browser have report events that indicate how each variant is scored and evaluated against clinical indications.
Report Events Key¶
| # | Section | Description |
|---|---|---|
| 1 | Report Events | Table of report events that can be viewed by clicking the ‘+’ sign next to the variant. |
| 2 | Selection Box | Checkbox to select report events for reporting. |
| 3 | Score | Priority assigned to the variant by an interpretation service, which may vary depending on the applied panel. Note: The Exomiser score is the "combined" phenotype and variant score. |
| 4 | Genomic Entity | Gene and Ensembl gene ID linking to the Ensembl gene page. |
| 5 | Mode of Inheritance | Known mode of inheritance for the gene concerning the clinical indication. |
| 6 | Panel Name | Panels applied to the case, used for prioritization. |
| 7 | Panel Version | Version of the panel applied. |
| 8 | Penetrance | Known penetrance data for the gene relative to the clinical indication. |
| 9 | Clinical Indication | Clinical indication assigned to the patient. |
| 10 | Interpretation Service | Service that assigned priority to the report event. |
| 11 | Show/Hide Variant Details | Button to view or hide additional information about a variant. |
Additional Annotations¶
Additional information such as allele frequencies, HGVS annotations, in silico predictions, and disease associations are retrieved from external databases held in CellBase.
Additional Annotations Key¶
| # | Section | Description |
|---|---|---|
| 1 | Positional and Allelic Details | Variant coordinates, alleles, and HGVS notation. |
| 2 | Most Severe Consequence Type | Most severe consequence of the variant relative to a transcript. |
| 3 | Consequence Types | Other known or predicted consequences of the variant across different transcripts and protein consequences. |
| 4 | Population Frequencies | Frequency of the variant in various populations, if available. |
| 5 | Variant Trait Association | Known association of the variant with diseases from external databases. |
| 6 | Gene Trait Association | Known associations of the gene with diseases. |