{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T02:22:04Z","timestamp":1769826124016,"version":"3.49.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> 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 (<jats:ext-link>https:\/\/dolphin.mmg-gbit.eu<\/jats:ext-link>).<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> 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\u2019 residue. These were validated using ClinVar data.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We applied this method to all potential human transcripts\u2019 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.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> 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.<\/jats:p>","DOI":"10.3389\/fbinf.2023.1127341","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T13:39:20Z","timestamp":1676986760000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Protein domains provide a new layer of information for classifying human variations in rare diseases"],"prefix":"10.3389","volume":"3","author":[{"given":"M\u00e9lanie","family":"Corcuff","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Garibal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Pierre","family":"Desvignes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9line","family":"Guien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coralie","family":"Grattepanche","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gwena\u00eblle","family":"Collod-B\u00e9roud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estelle","family":"M\u00e9noret","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Salgado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"B\u00e9roud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1016\/j.ajhg.2016.03.024","article-title":"Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the clinical sequencing exploratory research Consortium","volume":"98","author":"Amendola","year":"2016","journal-title":"Am. 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