{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T15:46:08Z","timestamp":1775922368269,"version":"3.50.1"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DK52913"],"award-info":[{"award-number":["R01 DK52913"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Advancing a Healthier Wisconsin Endowment"},{"name":"Linda T. and John A. Mellowes Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>Protein-coding genetic alterations are frequently observed in Clinical Genetics, but the high yield of variants of uncertain significance remains a limitation in decision making. RAS-family GTPases are cancer drivers, but only 54 variants, across all family members, fall within well-known hotspots. However, extensive sequencing has identified 881 non-hotspot variants for which significance remains to be investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we evaluate 935 missense variants from seven RAS genes, observed in cancer, RASopathies and the healthy adult population. We characterized hotspot variants, previously studied experimentally, using 63 sequence- and 3D structure-based scores, chosen by their breadth of biophysical properties. Applying scores that display best correlation with experimental measures, we report new valuable mechanistic inferences for both hot-spot and non-hotspot variants. Moreover, we demonstrate that 3D scores have little-to-no correlation with those based on DNA sequence, which are commonly used in Clinical Genetics. Thus, combined, these new knowledge bear significant relevance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>All genomic and 3D scores, and markdown for generating figures, are provided in our supplemental data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa972","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T20:18:22Z","timestamp":1605125902000},"page":"1367-1375","source":"Crossref","is-referenced-by-count":7,"title":["Structural bioinformatics enhances mechanistic interpretation of genomic variation, demonstrated through the analyses of 935 distinct RAS family mutations"],"prefix":"10.1093","volume":"37","author":[{"given":"Swarnendu","family":"Tripathi","sequence":"first","affiliation":[{"name":"Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"},{"name":"Precision Medicine Simulation Unit, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"}]},{"given":"Nikita R","family":"Dsouza","sequence":"additional","affiliation":[{"name":"Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"},{"name":"Precision Medicine Simulation Unit, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"}]},{"given":"Raul","family":"Urrutia","sequence":"additional","affiliation":[{"name":"Precision Medicine Simulation Unit, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"},{"name":"Department of Surgery, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7073-0525","authenticated-orcid":false,"given":"Michael T","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"},{"name":"Precision Medicine Simulation Unit, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"},{"name":"Clinical and Translational Sciences Institute, Genomic Sciences and Precision Medicine Center , Milwaukee, WI 53226, USA"},{"name":"Department of Biochemistry, Medical College of Wisconsin , Milwaukee, WI 53226, USA"}]}],"member":"286","published-online":{"date-parts":[[2020,12,7]]},"reference":[{"key":"2023051709345198200_btaa972-B1","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1002\/humu.23876","article-title":"Reports from the fifth edition of CAGI: the critical assessment of genome interpretation","volume":"40","author":"Andreoletti","year":"2019","journal-title":"Hum. 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