Dear All,

Greetings from a chilly East Anglia where the snow drops are beginning to bloom.

In this update:

- DECIPHER v11.1 Released

o More support for centres still working in GRCh37

§ How to search with GRCh37 coordinates

§ Visualising liftover changes

§ How to ‘fix’ variants which failed liftover

o Features for interpreting CNVs according to ACMG/ClinGen recommendations

§ ClinGen DS Genes and Regions (replacing ISCA)

§ DGV Gold and gnomAD structural Variants

§ sHet, LOEUF scores

o Developments for sequence variant interpretation

§ PS3/BS3 draft recommendations

§ ClinGen Expert Panel recommendations

§ REVEL scores

- Upcoming domain change - https://deciphergenomics.org

DECIPHER v11.1 Released 

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You can also view this on the web at: https://decipher.sanger.ac.uk/about/news

More support for centres still working in GRCh37

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DECIPHER moved to visualise genomic data in GRCh38 in December 2020. To help centres still working in GRCh37, it is now possible to search DECIPHER using GRCh37 coordinates by prefixing the coordinates with “grch37:”; these coordinates will be lifted over to GRCh38 before performing the search. In addition, an optional track showing the mapping to GRCh37/hg19 used to lift over variants is available in the genome browser. This track is based on UCSC’s chain files (https://genome.ucsc.edu/goldenPath/help/chain.html) and visualises the alignment back to GRCh37. This track can be turned on by clicking on the word “Tracks” at the top left of the genome browser and clicking on the + symbol next to the “Liftover mapping” track listed on the right of the popup, under “Available tracks”.

For variants that have been lifted over from GRCh37 to GRCh38, genome browsers in GRCh37 and GRCh38 are available, to allow the gene content and transcripts in both builds to be viewed. This view can be accessed by clicking on the ? icon next to a variant in the genotype table of a patient record. This view is also available to registered users for variants that the user has write access to, that have failed automatic liftover. The reason for the liftover failing is provided, along with the percentage match at which liftover will succeed. It is possible for the user to confirm the remapping, if they are in agreement with the liftover to GRCh38. When using the web interface to deposit variant data in GRCh37, if liftover fails using DECIPHER's 80% threshold for automatic remapping, it is possible to try remapping again without the 80% limit. The percentage at which the coordinates can be remapped is displayed, along with genome browsers in GRCh37 and GRCh38. The user can confirm the remapping if the location in GRCh38 is a good enough match. Please note, for matches below DECIPHER's 80% threshold for automatic remapping, the user should carefully check the remapping, paying particular attention to the gene content in the region.

Features for interpreting CNVs according to ACMG/ClinGen recommendations

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Additional structural variants tracks are now available on the genome browser to support the interpretation of CNVs according to ACMG/ClinGen recommendations (https://pubmed.ncbi.nlm.nih.gov/31690835). These include a ClinVar structural variant track, a DGV Gold track and a gnomAD structural variants track. Filters are available on all tracks. Clinically relevant and population structural variants have different colouring for clarity. A ClinGen dosage sensitivity region genome browser track is also now available. The ISCA track has been removed as this data has either been submitted to ClinVar or incorporated into ClinGen dosage sensitivity curations. The new tracks can be seen for a deletion on chromosome 7 here: https://decipher.sanger.ac.uk/patient/304406/genotype/150871/browser

ClinGen gene annotations are now displayed on the gene page and in genes tables. This includes ClinGen gene-disease validity and ClinGen dosage sensitivity scores. Also included are further predictive gene scores, LOEUF and sHet. LOEUF is quantitative measure of the observed depletion (or enrichment) of loss-of-function variants in gnomAD compared to a null mutational model, published by Karczewski et al., 2020 (https://pubmed.ncbi.nlm.nih.gov/32461654). sHet is a per gene estimate of the impact on fitness for individuals who harbor heterozygous loss-of-function variants in the gene, published by Weghorn, Balick et al., 2019 (https://pubmed.ncbi.nlm.nih.gov/31004148). The gene page has also been reorganised so that similar information is more clearly grouped together. These changes and additions can be viewed for SCN2A here: https://decipher.sanger.ac.uk/gene/SCN2A/overview/clinical-info. The changes to the genes table can be viewed here for a patient with a duplication on chromosome 22: https://decipher.sanger.ac.uk/patient/283569/genotype/150989/genes

Developments for sequence variant interpretation

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The ClinGen Sequence Variant Interpretation Working Group (https://www.clinicalgenome.org/working-groups/sequence-variant-interpretation) draft recommendations for the application of the functional evidence PS3/BS3 criterion are now displayed on the pathogenicity evidence tab. An interactive version of the decision tree as described in Brnich et al., 2019 (https://pubmed.ncbi.nlm.nih.gov/31892348) is available. This can be accessed by clicking on the “Further information” icon next to the PS3/BS3 criterion: https://decipher.sanger.ac.uk/patient/307098/genotype/211767/pathogenicity

For genes that have ClinGen expert panel specification, a link to the relevant ClinGen curation expert panel webpage is displayed on the pathogenicity evidence tab. This facilitates access to these specifications, when interpreting a variant in these genes.

Finally, REVEL scores are now displayed on the annotation tab. REVEL is a method for predicting the pathogenicity of missense variants. It combines pathogenicity predictions from 18 individual scores, including 8 conservation scores and 10 functional scores as described in Ioannidis et al., 2016 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065685). REVEL scores for a missense variant in CDK13 can be viewed here: https://decipher.sanger.ac.uk/patient/260858/genotype/198103/annotation/vep-prediction

Upcoming domain change - https://deciphergenomics.org

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Clinical genetics centres from around the world deposit data to DECIPHER.  In view of this, the web domain will be updated over the coming weeks from https://decipher.sanger.ac.uk to https://deciphergenomics.org. This change is already reflected in the ethics documentation, including the patient information sheet, consent form and assent form.

At present anyone visiting https://deciphergenomics.org will be re-directed to https://decipher.sanger.ac.uk. Once the domain has changed, users visiting https://decipher.sanger.ac.uk will be redirected to the new domain, to ensure that our users do not have any issues accessing the DECIPHER website.

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We look forward to your feedback and suggestions for improvement. Please use the "Feedback" button which is available on every page and fill in the simple form to get in touch with us. Your details will be filled in automatically if you are logged in.

Best Regards

Julia, on behalf of the DECIPHER team

Julia Foreman PhD

DECIPHER Project Manager

Email: decipher@sanger.ac.uk

Web: https://decipher.sanger.ac.uk

Twitter: @decipher_wtsi