Dataset Information

Protein domains provide a new layer of information for classifying human variations in rare diseases.

ABSTRACT: Introduction: Using the ACMG-AMP guidelines for the interpretation of sequence variants, it remains difficult to meet the criterion associated with the protein domain, PM1, which is assigned in only about 10% of cases, whereas the criteria related to variant frequency, PM2/BA1/BS1, is reported in 50% of cases. To improve the classification of human missense variants using protein domains information, we developed the DOLPHIN system (https://dolphin.mmg-gbit.eu). Methods: We used Pfam alignments of eukaryotes to define DOLPHIN scores to identify protein domain residues and variants that have a significant impact. In parallel, we enriched gnomAD variants frequencies for each domains' residue. These were validated using ClinVar data. Results: We applied this method to all potential human transcripts' variants, resulting in 30.0% being assigned a PM1 label, whereas 33.2% were eligible for a new benign support criterion, BP8. We also showed that DOLPHIN provides an extrapolated frequency for 31.8% of the variants, compared to the original frequency available in gnomAD for 7.6% of them. Discussion: Overall, DOLPHIN allows a simplified use of the PM1 criterion, an expanded application of the PM2/BS1 criteria and the creation of a new BP8 criterion. DOLPHIN could facilitate the classification of amino acid substitutions in protein domains that cover nearly 40% of proteins and represent the sites of most pathogenic variants.

SUBMITTER: Corcuff M

PROVIDER: S-EPMC9990413 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Protein domains provide a new layer of information for classifying human variations in rare diseases.

Corcuff Mélanie M Garibal Marc M Desvignes Jean-Pierre JP Guien Céline C Grattepanche Coralie C Collod-Béroud Gwenaëlle G Ménoret Estelle E Salgado David D Béroud Christophe C

Frontiers in bioinformatics 20230221

<b>Introduction:</b> Using the ACMG-AMP guidelines for the interpretation of sequence variants, it remains difficult to meet the criterion associated with the protein domain, PM1, which is assigned in only about 10% of cases, whereas the criteria related to variant frequency, PM2/BA1/BS1, is reported in 50% of cases. To improve the classification of human missense variants using protein domains information, we developed the DOLPHIN system (https://dolphin.mmg-gbit.eu). <b>Methods:</b> We used Pf ...[more]

PMID: 36896423

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Dataset Information

Protein domains provide a new layer of information for classifying human variations in rare diseases.

Publications

Protein domains provide a new layer of information for classifying human variations in rare diseases.

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