{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T12:31:51Z","timestamp":1774441911864,"version":"3.50.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"22-23","license":[{"start":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T00:00:00Z","timestamp":1607558400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\u2019s National Human Genome Research Institute Centers of Excellence"},{"name":"Genomic Science Initiative","award":["HG004233"],"award-info":[{"award-number":["HG004233"]}]},{"name":"Genomic Science Initiative","award":["HG010461"],"award-info":[{"award-number":["HG010461"]}]},{"name":"Canadian Institutes of Health Research Foundation Program"},{"DOI":"10.13039\/501100002784","name":"Canada Excellence Research Chairs Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002784","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>When rare missense variants are clinically interpreted as to their pathogenicity, most are classified as variants of uncertain significance (VUS). Although functional assays can provide strong evidence for variant classification, such results are generally unavailable. Multiplexed assays of variant effect can generate experimental \u2018variant effect maps\u2019 that score nearly all possible missense variants in selected protein targets for their impact on protein function. However, these efforts have not always prioritized proteins for which variant effect maps would have the greatest impact on clinical variant interpretation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Here, we mined databases of clinically interpreted variants and applied three strategies, each building on the previous, to prioritize genes for systematic functional testing of missense variation. The strategies ranked genes (i) by the number of unique missense VUS that had been reported to ClinVar; (ii) by movability- and reappearance-weighted impact scores, to give extra weight to reappearing, movable VUS and (iii) by difficulty-adjusted impact scores, to account for the more resource-intensive nature of generating variant effect maps for longer genes. Our results could be used to guide systematic functional testing of missense variation toward greater impact on clinical variant interpretation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Source code available at: https:\/\/github.com\/rothlab\/mave-gene-prioritization<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa1008","type":"journal-article","created":{"date-parts":[[2020,11,21]],"date-time":"2020-11-21T04:45:58Z","timestamp":1605933958000},"page":"5448-5455","source":"Crossref","is-referenced-by-count":10,"title":["Prioritizing genes for systematic variant effect mapping"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3554-0464","authenticated-orcid":false,"given":"Da","family":"Kuang","sequence":"first","affiliation":[{"name":"Donnelly Centre, University of Toronto , Toronto, ON M5S 3E1, Canada"},{"name":"Department of Molecular Genetics, University of Toronto , Toronto, ON M5S 1A8, Canada"},{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System , Toronto, ON M5G 1X5, Canada"},{"name":"Department of Computer Science, University of Toronto , Toronto, ON M5T 3A1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Truty","sequence":"additional","affiliation":[{"name":"Invitae Corporation , San Francisco, CA 94103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochen","family":"Weile","sequence":"additional","affiliation":[{"name":"Donnelly Centre, University of Toronto , Toronto, ON M5S 3E1, Canada"},{"name":"Department of Molecular Genetics, University of Toronto , Toronto, ON M5S 1A8, Canada"},{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System , Toronto, ON M5G 1X5, Canada"},{"name":"Department of Computer Science, University of Toronto , Toronto, ON M5T 3A1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britt","family":"Johnson","sequence":"additional","affiliation":[{"name":"Invitae Corporation , San Francisco, CA 94103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith","family":"Nykamp","sequence":"additional","affiliation":[{"name":"Invitae Corporation , San Francisco, CA 94103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Araya","sequence":"additional","affiliation":[{"name":"Invitae Corporation , San Francisco, CA 94103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert L","family":"Nussbaum","sequence":"additional","affiliation":[{"name":"Invitae Corporation , San Francisco, CA 94103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6628-649X","authenticated-orcid":false,"given":"Frederick P","family":"Roth","sequence":"additional","affiliation":[{"name":"Donnelly Centre, University of Toronto , Toronto, ON M5S 3E1, Canada"},{"name":"Department of Molecular Genetics, University of Toronto , Toronto, ON M5S 1A8, Canada"},{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System , Toronto, ON M5G 1X5, Canada"},{"name":"Department of Computer Science, University of Toronto , Toronto, ON M5T 3A1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,12,10]]},"reference":[{"key":"2023062707101944000_btaa1008-B1","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1161\/CIRCULATIONAHA.105.547448","article-title":"Gene mutations in apical hypertrophic cardiomyopathy","volume":"112","author":"Arad","year":"2005","journal-title":"Circulation"},{"key":"2023062707101944000_btaa1008-B2","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1158\/1541-7786.MCR-17-0245","article-title":"A massively parallel fluorescence assay to characterize the effects of synonymous mutations on TP53 expression","volume":"15","author":"Bhagavatula","year":"2017","journal-title":"Mol. 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