Short Tandem Repeat Variant Grid¶
This page provides the ability to:
- Review the STR variants identified by ExpansionHunter as part of the DRAGEN software in the Genomics England Rare Disease Pipeline
- Review additional annotations and linkouts to external resources for each variant (see STR grid guide below for further details)
- View pileup plots for each STR per participant
- Assign an ACGS/ACMG classification to a variant, including selecting contribution to phenotype, validation details, 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
STR grid guide¶
The STR grid displays only Tiered variants for the case, and displays these in order (Tier 1, Tier 2, Tier Null). Only loci that are marked green in PanelApp for the applied gene panel and have a PASS quality status from ExpansionHunter are considered for Tiering. For further details on this, and the thresholds used for each Tier (these are defined in PanelApp for the STR locus), please visit the Rare Disease Genome Analysis Guide.
Please use the below key in conjunction with the below sections to learn more about the columns in the variant grid.
N.B. it is recommended that all expansion-positive results and normal alleles that are close to the threshold and sequencing read length, which are deemed as possibly clinically relevant, are assessed by reviewing STR pileup plots, and, if required, an orthogonal test is performed. For further details please see the Auncertainty page in the Rare Disease Genome Analysis Guide.
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) |
| 2 | Tier | This can be Tier 1, Tier 2, or Tier Null. For further details, please visit the Tier section below. |
| 3 | Variant | The VCF format of the variants, with a button that can be used to link-out to gnomAD, and a button to copy the variant coordinates in Alamut format |
| 4 | STR locus | HGNC gene symbol(s) and repeat motif for the STR locus. Clicking on the pill opens the STR overlay. For further details, please visit the STR locus section below. |
| 5 | STR locus colour | STR locus pills are coloured green according to their PanelApp green gene status. For further details, please visit the STR locus section below. |
| 6 | Thresholds (Normal / Pathogenic) | The normal and pathogenic thresholds for the variant (these are defined in PanelApp for the STR locus). For further details, please visit the measurement of uncertainty page in the Rare Disease Genome Analysis Guide. |
| 7 | Counts / Repeat count interval (Proband / Mother / Father etc.) | A column for the proband and one per family member, containing the repeat count per allele, plus the confidence interval within brackets. More details can be found in the repeat counts card below. |
| 8 | Pileup plot | Link-out to the pileup plots for the STR locus per participant. For further details, please visit the pileup plots section below. |
| 9 | Reveal button | To expose the repeat counts and link to pileup plot for an unaffected individual, click the eye icon. These are only visible by default for affected individuals. For further details, please visit the repeat counts section below. |
Tier¶
This can be Tier 1, Tier 2, or Tier Null. Variants are displayed in this order. Only loci that are marked green in PanelApp for the applied gene panel and have a PASS quality status from ExpansionHunter are considered for Tiering. For more details on this, and the thresholds used for each Tier, please visit the Rare Disease Genome Analysis Guide
Tier overlay¶
When clicking on the tooltip next to the Tier, the Tier overlay opens. The Tier overlay displays details about the Genomics England Tiering outcome for the STR.
The highest Tier assigned to the STR, 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 STR 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 (segregation and penetrance always display as Not applicable as they are not considered by the Tiering algorithm as part of STR Tiering).
There is no Source column in the Tier overlay as the source for all prioritisation results for STRs is Standard Tiering.
N.B. a gene can be a different rating in PanelApp (green / amber / red) from the corresponding STR locus
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 |
| 4 | Gene | Gene associated with the STR locus for the Genomics England Rare Disease Tiering result |
| 5 | STR locus | STR locus associated with the Genomcis England Rare Disease Tiering result |
| 6 | Entity colour | The entity pill is coloured green when the gene or STR locus 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 | Segregation is not considered by the Tiering algorithm as part of STR Tiering |
| 8 | Variant MOI | The mode of inheritance that the variant fits with and that led to this Tiering outcome. See the STR Tiering algorithm page in the Rare Disease Genome Analysis Guide. |
| 9 | Variant penetrance | This is arbitrarily assigned depending on the penetrance of the case itself, and does not affect the Tiering outcome of the STR - penetrance is not considered by the Tiering algorithm as part of STR Tiering |
| 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 |
STR locus¶
HGNC gene symbol(s) and repeat motif for the STR locus. Clicking on the pill opens the STR overlay.
Colour¶
The pill is coloured green when the STR locus is green in at least one PanelApp panel of the most recent version at the time of case ingestion.
STR overlay¶
The STR overlay contains more detailed information for the STR locus, plus the associated gene. For the STR locus, we provide a table displaying the PanelApp panels the STR is present in. For the gene, we provide Ensembl ID, PanelApp panels the gene is present in, OMIM associated diseases for the gene, and links to external resources for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER, GeneReviews). The data used for PanelApp annotation is updated every hour (data is static once the case is ingested into the New IB).
Each STR locus in the STR grid is associated with a single gene. Should the repeat region fall within multiple genes, this would appear as separate STR loci in the STR grid, with separate STR overlays.
Key
| # | Section | Description |
|---|---|---|
| 1 | STR locus and colour | Each STR locus in the STR grid is associated with a single gene. The pill is coloured green when the STR locus is green in at least one PanelApp panel of the most recent version at the time of case ingestion. |
| 2 | External links (STR locus) | Linkouts to the page in PanelApp for the STR locus |
| 3 | PanelApp panels (STR locus) | This section displays the PanelApp panels for the STR locus (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 STR. If there is no MOI recorded in PanelApp, then this will be displayed as Unknown. If the STR has been removed from the panel in the most recent version at the time of case ingestion, then a '-' is displayed in the STR status column, and the STR MOI will be displayed as Unknown. If the STR is present in no PanelApp panels, then None is displayed in place of all data. |
| 4 | Gene and colour | HGNC symbol for the gene that the STR locus is present in. The 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. |
| 5 | Gene ID | Ensembl gene ID |
| 6 | External links (gene) | Linkouts to external resources and databases for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER, GeneReviews) |
| 7 | PanelApp panels (gene) | 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. |
| 8 | OMIM associated diseases (gene) | 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. |
Repeat counts¶
ExpansionHunter is used in the pipeline to estimate the size of short tandem repeats (STRs) for each participant. It provides an estimated repeat size for each allele, which is displayed in the Counts / Repeat count interval column, plus an estimated range (REPCI - repeat count interval), which is displayed in brackets next to the estimated repeat size. The range reflects uncertainty due to sequencing errors, alignment challenges, and limitations of short-read sequencing in repetitive regions.
For clinical sensitivity, the maximum value in the range is used by the pipeline to decide the Tier of the STR (i.e. worst case scenario), in order to account for this uncertainty. This value is indicated within the New IB by an underline, which upon hover indicates that the value is Used by Tiering. As STRs are assigned Tier based on the upper bound, sometimes the assigned Tier might not correspond to the thresholds that the estimated size sits within (i.e. the upper bound exceeds the Threshold for a Tier, but the estimated size sits below it). This approach balances sensitivity (not missing real expansions) with specificity (avoiding false positives). For more details, please visit the measurements of uncertainty page in the Rare Disease Genome Analysis Guide.
The repeat counts for the proband and any affected individuals are visible by default. However, repeat counts for any unaffected inidividuals are hidden by default, to minimize potential incidental findings during the analysis process. Should these need to be viewed to assist with analysis, the repeat counts can be exposed per variant and inidividual by clicking the eye icon.
Pileup plots¶
Link-outs to pileup plot are provided per STR locus per participant, within the Counts / Repeat count interval column. Clicking on the links will open up the plot file in a new tab. To open the pileup plots for unaffected individuals, the link will need to be made visible first by clicking the eye icon.
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 |