{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T04:04:55Z","timestamp":1770782695265,"version":"3.50.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2019,5,29]],"date-time":"2019-05-29T00:00:00Z","timestamp":1559088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Nanjing Medical Science and Technology Development","award":["YKK15082"],"award-info":[{"award-number":["YKK15082"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>A variety of in silico tools have been developed and frequently used to aid high-throughput rapid variant classification, but their performances vary, and their ability to classify variants of uncertain significance were not systemically assessed previously due to lack of validation data. This has been changed recently by advances of functional assays, where functional impact of genetic changes can be measured in single-nucleotide resolution using saturation genome editing (SGE) assay.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We demonstrated the neural network model AIVAR (Artificial Intelligent VARiant classifier) was highly comparable to human experts on multiple verified datasets. Although highly accurate on known variants, AIVAR together with CADD and PhyloP showed non-significant concordance with SGE function scores. Moreover, our results indicated that neural network model trained from functional assay data may not produce accurate prediction on known variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>All source code of AIVAR is deposited and freely available at https:\/\/github.com\/TopGene\/AIvar.<\/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\/btz442","type":"journal-article","created":{"date-parts":[[2019,5,23]],"date-time":"2019-05-23T11:23:07Z","timestamp":1558610587000},"page":"5163-5170","source":"Crossref","is-referenced-by-count":7,"title":["Assessing concordance among human, <i>in silico<\/i> predictions and functional assays on genetic variant classification"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5453-6431","authenticated-orcid":false,"given":"Jiaqi","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianliangwen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobin","family":"You","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Zi","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangming","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoji","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qihuan","family":"Zhi","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital , Nanjing, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Drum Tower Clinical Medical College of Nanjing Medical University , Nanjing, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaixuan","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianmei","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luhua","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianfeng","family":"Sang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Nanjing Drum Tower Hospital , Nanjing, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1115-8084","authenticated-orcid":false,"given":"Yujian","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Research, Top Gene Tech (Guangzhou) Co., Ltd , Guangzhou, Guangdong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,5,29]]},"reference":[{"key":"2023013108375617800_btz442-B1","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"2023013108375617800_btz442-B2","doi-asserted-by":"crossref","first-page":"S3.","DOI":"10.1186\/1471-2164-14-S3-S3","article-title":"Identifying Mendelian disease genes with the Variant Effect Scoring Tool","volume":"14","author":"Carter","year":"2013","journal-title":"BMC Genomics"},{"key":"2023013108375617800_btz442-B3","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nbt.3514","article-title":"Articles Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases","volume":"34","author":"Chen","year":"2016","journal-title":"Nat. Biotechnol"},{"key":"2023013108375617800_btz442-B4","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1101\/gr.092619.109","article-title":"Identification of deleterious mutations within three human genomes","volume":"19","author":"Chun","year":"2009","journal-title":"Genome Res"},{"key":"2023013108375617800_btz442-B5","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/ng.3643","article-title":"A reference panel of 64,976 haplotypes for genotype imputation","volume":"48","author":"McCarthy","year":"2016","journal-title":"Nat. Genet"},{"key":"2023013108375617800_btz442-B6","doi-asserted-by":"crossref","first-page":"e1001025.","DOI":"10.1371\/journal.pcbi.1001025","article-title":"Identifying a high fraction of the human genome to be under selective constraint using GERP++","volume":"6","author":"Davydov","year":"2010","journal-title":"PLoS Comput. Biol"},{"key":"2023013108375617800_btz442-B7","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","article-title":"Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies","volume":"24","author":"Dong","year":"2015","journal-title":"Hum. Mol. Genet"},{"key":"2023013108375617800_btz442-B8","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.1181498","article-title":"Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays","volume":"327","author":"Drmanac","year":"2010","journal-title":"Science"},{"key":"2023013108375617800_btz442-B9","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41586-018-0461-z","article-title":"Accurate classification of BRCA1 variants with saturation genome editing","volume":"562","author":"Findlay","year":"2018","journal-title":"Nature"},{"key":"2023013108375617800_btz442-B10","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nature13695","article-title":"Saturation editing of genomic regions by multiplex homology-directed repair","volume":"513","author":"Findlay","year":"2014","journal-title":"Nature"},{"key":"2023013108375617800_btz442-B11","doi-asserted-by":"crossref","first-page":"i54","DOI":"10.1093\/bioinformatics\/btp190","article-title":"Identifying novel constrained elements by exploiting biased substitution patterns","volume":"25","author":"Garber","year":"2009","journal-title":"Bioinformatics"},{"key":"2023013108375617800_btz442-B12","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Gibbs","year":"2015","journal-title":"Nature"},{"key":"2023013108375617800_btz442-B13","doi-asserted-by":"crossref","first-page":"D140","DOI":"10.1093\/nar\/gkj112","article-title":"miRBase: microRNA sequences, targets and gene nomenclature","volume":"34","author":"Griffiths-Jones","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/bib\/bbq072","article-title":"PHAST and RPHAST: phylogenetic analysis with space\/time models","volume":"12","author":"Hubisz","year":"2011","journal-title":"Brief. Bioinform"},{"key":"2023013108375617800_btz442-B15","doi-asserted-by":"crossref","first-page":"D306","DOI":"10.1093\/nar\/gkr948","article-title":"InterPro in 2011: new developments in the family and domain prediction database","volume":"40","author":"Hunter","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B16","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: an ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet"},{"key":"2023013108375617800_btz442-B17","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/ng.3477","article-title":"A spectral approach integrating functional genomic annotations for coding and noncoding variants","volume":"48","author":"Ionita-Laza","year":"2016","journal-title":"Nat. Genet"},{"key":"2023013108375617800_btz442-B18","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The human genome browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res"},{"key":"2023013108375617800_btz442-B19","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet"},{"key":"2023013108375617800_btz442-B20","doi-asserted-by":"crossref","first-page":"eaan6566","DOI":"10.1126\/scitranslmed.aan6566","article-title":"A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer","volume":"9","author":"Kohsaka","year":"2017","journal-title":"Sci. Transl. Med"},{"key":"2023013108375617800_btz442-B21","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc"},{"key":"2023013108375617800_btz442-B22","doi-asserted-by":"crossref","first-page":"D862","DOI":"10.1093\/nar\/gkv1222","article-title":"ClinVar: public archive of interpretations of clinically relevant variants","volume":"44","author":"Landrum","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B23","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"2023013108375617800_btz442-B24","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am. J. Hum. Genet"},{"key":"2023013108375617800_btz442-B25","article-title":"Consistency of BRCA1 and BRCA2 variant classifications among clinical diagnostic laboratories","volume":"1","author":"Lincoln","year":"2017","journal-title":"JCO Precis. Oncol"},{"key":"2023013108375617800_btz442-B26","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/humu.22932","article-title":"dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs","volume":"37","author":"Liu","year":"2016","journal-title":"Hum. Mutat"},{"key":"2023013108375617800_btz442-B27","doi-asserted-by":"crossref","first-page":"D896","DOI":"10.1093\/nar\/gkw1133","article-title":"The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog)","volume":"45","author":"MacArthur","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B28","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/ng.3700","article-title":"Prospective functional classification of all possible missense variants in PPARG","volume":"48","author":"Majithia","year":"2016","journal-title":"Nat. Genet"},{"key":"2023013108375617800_btz442-B29","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/s41588-018-0122-z","article-title":"Multiplex assessment of protein variant abundance by massively parallel sequencing","volume":"50","author":"Matreyek","year":"2018","journal-title":"Nat. Genet"},{"key":"2023013108375617800_btz442-B30","doi-asserted-by":"crossref","first-page":"D756","DOI":"10.1093\/nar\/gkt1114","article-title":"RefSeq: an update on mammalian reference sequences","volume":"42","author":"Pruitt","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B31","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cels.2016.01.009","article-title":"TensorFlow: biology\u2019s gateway to deep learning?","volume":"2","author":"Rampasek","year":"2016","journal-title":"Cell Syst"},{"key":"2023013108375617800_btz442-B32","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med"},{"key":"2023013108375617800_btz442-B33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-014-0087-1","article-title":"Computational approaches to interpreting genomic sequence variation","volume":"6","author":"Ritchie","year":"2014","journal-title":"Genome Med"},{"key":"2023013108375617800_btz442-B34","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"2023013108375617800_btz442-B35","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/humu.23123","article-title":"A comprehensive functional analysis of NTRK1 missense mutations causing Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV)","volume":"38","author":"Shaikh","year":"2017","journal-title":"Hum. Mutat"},{"key":"2023013108375617800_btz442-B36","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1093\/nar\/29.1.308","article-title":"dbSNP: the NCBI database of genetic variation","volume":"29","author":"Sherry","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B37","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1093\/bioinformatics\/btt182","article-title":"Predicting the functional consequences of cancer-associated amino acid substitutions","volume":"29","author":"Shihab","year":"2013","journal-title":"Bioinformatics"},{"key":"2023013108375617800_btz442-B38","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/humu.23143","article-title":"Are functional assays for pathogenicity assessment of genetic variants overrated?","volume":"38","author":"Sobrido","year":"2017","journal-title":"Hum. Mutat"},{"key":"2023013108375617800_btz442-B39","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ajhg.2017.07.014","article-title":"Variant interpretation: functional assays to the rescue","volume":"101","author":"Starita","year":"2017","journal-title":"Am. J. Hum. Genet"},{"key":"2023013108375617800_btz442-B40","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B41","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/nar\/24.1.238","article-title":"TRANSFAC: a database on transcription factors and their DNA binding sites","volume":"24","author":"Wingender","year":"1996","journal-title":"Nucleic Acids Res"},{"key":"2023013108375617800_btz442-B42","doi-asserted-by":"crossref","first-page":"D183","DOI":"10.1093\/nar\/gkl873","article-title":"Sno\/scaRNAbase: a curated database for small nucleolar RNAs and cajal body-specific RNAs","volume":"35","author":"Xie","year":"2007","journal-title":"Nucleic Acids Res"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz442\/28837687\/btz442.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/24\/5163\/48977900\/bioinformatics_35_24_5163.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/24\/5163\/48977900\/bioinformatics_35_24_5163.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T17:55:20Z","timestamp":1675187720000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/24\/5163\/5505418"}},"subtitle":[],"editor":[{"given":"Jonathan","family":"Wren","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2019,5,29]]},"references-count":42,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2019,12,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz442","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,12,15]]},"published":{"date-parts":[[2019,5,29]]}}}