{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:46:15Z","timestamp":1790952375443,"version":"4.1.0"},"reference-count":55,"publisher":"American Association for the Advancement of Science (AAAS)","license":[{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["csbj.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Comput Struct Biotechnol J"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:p>\n                    Next-generation genome sequencing has revolutionized genetic testing, identifying numerous rare disease-associated gene variants. However, to impute pathogenicity, computational approaches remain inadequate and functional testing of gene variant is required to provide the highest level of evidence. The emergence of AlphaFold2 has transformed the field of protein structure determination, and here we outline a strategy that leverages predicted protein structure to enhance genetic variant classification. We used the gene\n                    <jats:italic toggle=\"yes\">IRF6<\/jats:italic>\n                    as a case study due to its clinical relevance, its critical role in cleft lip\/palate malformation, and the availability of experimental data on the pathogenicity of\n                    <jats:italic toggle=\"yes\">IRF6<\/jats:italic>\n                    gene variants through phenotype rescue experiments in\n                    <jats:italic toggle=\"yes\">irf6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic toggle=\"yes\">-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    zebrafish. We compared results from over 30 pathogenicity prediction tools on 37\n                    <jats:italic toggle=\"yes\">IRF6<\/jats:italic>\n                    missense variants.\n                    <jats:italic toggle=\"yes\">IRF6<\/jats:italic>\n                    lacks an experimentally derived structure, so we used predicted structures to explore associations between mutational clustering and pathogenicity. We found that among these variants, 19 of 37 were unanimously predicted as deleterious by computational tools. Comparing\n                    <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                    predictions with experimental findings, 12 variants predicted as pathogenic were experimentally determined as benign. Even with the recently published AlphaMissense model, 15\/18 (83%) of the predicted pathogenic variants were experimentally determined as benign. In comparison, mapping variants to the protein revealed deleterious mutation clusters around the protein binding domain, whereas N-terminal variants tend to be benign, suggesting the importance of structural information in determining pathogenicity of mutations in this gene. In conclusion, incorporating gene-specific structural features of known pathogenic\/benign mutations may provide meaningful insights into pathogenicity predictions in a gene-specific manner and facilitate the interpretation of variant pathogenicity.\n                  <\/jats:p>","DOI":"10.1016\/j.csbj.2024.01.019","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T11:42:09Z","timestamp":1706960529000},"page":"892-904","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":13,"title":["Genetic variant classification by predicted protein structure: A case study on IRF6"],"prefix":"10.34133","volume":"23","author":[{"given":"Hemma","family":"Murali","sequence":"first","affiliation":[{"name":"Graduate Program in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA 19104, United States"},{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, United States"},{"name":"Master of Biotechnology Program, University of Pennsylvania, Philadelphia, PA 19104, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States"},{"name":"Center for Craniofacial Innovation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, United States"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"e_1_4_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306555"},{"key":"e_1_4_2_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.628946"},{"key":"e_1_4_2_4_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2019.303305"},{"key":"e_1_4_2_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-9-228"},{"key":"e_1_4_2_6_2","doi-asserted-by":"publisher","DOI":"10.3343\/alm.2021.41.1.25"},{"key":"e_1_4_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-24100-1_2"},{"key":"e_1_4_2_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-012751"},{"key":"e_1_4_2_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13505"},{"key":"e_1_4_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-018-1375-3"},{"key":"e_1_4_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2017.116"},{"key":"e_1_4_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3046"},{"key":"e_1_4_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_4_2_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphg.93"},{"key":"e_1_4_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.06.011"},{"key":"e_1_4_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/jlb\/lsx038"},{"key":"e_1_4_2_17_2","doi-asserted-by":"publisher","DOI":"10.1057\/s41292-016-0020-5"},{"key":"e_1_4_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg509"},{"key":"e_1_4_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_4_2_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"e_1_4_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx536"},{"key":"e_1_4_2_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1001025"},{"key":"e_1_4_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0167-z"},{"key":"e_1_4_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_4_2_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-14-S3-S3"},{"key":"e_1_4_2_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"e_1_4_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2574"},{"key":"e_1_4_2_28_2","doi-asserted-by":"publisher","DOI":"10.1101\/2022.11.14.516473"},{"key":"e_1_4_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_4_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26237"},{"key":"e_1_4_2_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26257"},{"issue":"1","key":"e_1_4_2_32_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The 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Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.","name":"copyright","label":"Copyright"}]}}