{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T06:28:51Z","timestamp":1785047331345,"version":"3.55.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: The prioritization and identification of disease-causing mutations is one of the most significant challenges in medical genomics. Currently available methods address this problem for non-synonymous single nucleotide variants (SNVs) and variation in promoters\/enhancers; however, recent research has implicated synonymous (silent) exonic mutations in a number of disorders.<\/jats:p>\n               <jats:p>Results: We have curated 33 such variants from literature and developed the Silent Variant Analyzer (SilVA), a machine-learning approach to separate these from among a large set of rare polymorphisms. We evaluate SilVA\u2019s performance on in silico \u2018infection\u2019 experiments, in which we implant known disease-causing mutations into a human genome, and show that for 15 of 33 disorders, we rank the implanted mutation among the top five most deleterious ones. Furthermore, we apply the SilVA method to two additional datasets: synonymous variants associated with Meckel syndrome, and a collection of silent variants clinically observed and stratified by a molecular diagnostics laboratory, and show that SilVA is able to accurately predict the harmfulness of silent variants in these datasets.<\/jats:p>\n               <jats:p>Availability: SilVA is open source and is freely available from the project website: http:\/\/compbio.cs.toronto.edu\/silva<\/jats:p>\n               <jats:p>Contact: \u00a0silva-snv@cs.toronto.edu<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btt308","type":"journal-article","created":{"date-parts":[[2013,6,5]],"date-time":"2013-06-05T02:31:51Z","timestamp":1370399511000},"page":"1843-1850","source":"Crossref","is-referenced-by-count":80,"title":["Identification of deleterious synonymous variants in human genomes"],"prefix":"10.1093","volume":"29","author":[{"given":"Orion J.","family":"Buske","sequence":"first","affiliation":[{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AshokKumar","family":"Manickaraj","sequence":"additional","affiliation":[{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Mital","sequence":"additional","affiliation":[{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter N.","family":"Ray","sequence":"additional","affiliation":[{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"},{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brudno","sequence":"additional","affiliation":[{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"},{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"},{"name":"1 Department of Computer Science, University of Toronto, Toronto, ON M5S 3H5, 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 1L7, 3Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, 4Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 and 5Donnelly Centre and the Banting and Best Department of Medical Research, University of Toronto, Toronto, ON M5S 3E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,6,4]]},"reference":[{"key":"2023012810451018600_btt308-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":"2023012810451018600_btt308-B2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nature09000","article-title":"Deciphering the splicing code","volume":"465","author":"Barash","year":"2010","journal-title":"Nature"},{"key":"2023012810451018600_btt308-B3","doi-asserted-by":"crossref","first-page":"i325","DOI":"10.1093\/bioinformatics\/btq200","article-title":"Model-based detection of alternative splicing signals","volume":"26","author":"Barash","year":"2010","journal-title":"Bioinformatics"},{"key":"2023012810451018600_btt308-B4","doi-asserted-by":"crossref","first-page":"28741","DOI":"10.1074\/jbc.M110.154575","article-title":"A synonymous single nucleotide polymorphism in \u03b4F508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein","volume":"285","author":"Bartoszewski","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2023012810451018600_btt308-B5","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrg775","article-title":"Listening to silence and understanding nonsense: exonic mutations that affect splicing","volume":"3","author":"Cartegni","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"2023012810451018600_btt308-B6","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nrg1770","article-title":"Hearing silence: non-neutral evolution at synonymous sites in mammals","volume":"7","author":"Chamary","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"2023012810451018600_btt308-B7","doi-asserted-by":"crossref","first-page":"27:1","DOI":"10.1145\/1961189.1961199","article-title":"LIBSVM: a library for support vector machines","volume":"2","author":"Chang","year":"2011","journal-title":"ACM Trans. Intell. Syst. Technol."},{"key":"2023012810451018600_btt308-B8","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/nrg3046","article-title":"Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data","volume":"12","author":"Cooper","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"2023012810451018600_btt308-B9","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1101\/gr.3577405","article-title":"Distribution and intensity of constraint in mammalian genomic sequence","volume":"15","author":"Cooper","year":"2005","journal-title":"Genome Res."},{"key":"2023012810451018600_btt308-B10","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0006-291X(02)00226-7","article-title":"Silent mutations affect in vivo protein folding in Escherichia coli","volume":"293","author":"Cortazzo","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023012810451018600_btt308-B11","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":"2023012810451018600_btt308-B12","doi-asserted-by":"crossref","first-page":"e18931","DOI":"10.1371\/journal.pone.0018931","article-title":"An unusual splice defect in the mitofusin 2 gene (MFN2) is associated with degenerative axonopathy in Tyrolean grey cattle","volume":"6","author":"Dr\u00f6gem\u00fcller","year":"2011","journal-title":"PloS One"},{"key":"2023012810451018600_btt308-B13","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nature09534","article-title":"A map of human genome variation from population-scale sequencing","volume":"467","author":"Durbin","year":"2010","journal-title":"Nature"},{"key":"2023012810451018600_btt308-B14","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/humu.10295","article-title":"Nonclassical splicing mutations in the coding and noncoding regions of the ATM gene: maximum entropy estimates of splice junction strengths","volume":"23","author":"Eng","year":"2004","journal-title":"Hum. Mutat."},{"key":"2023012810451018600_btt308-B15","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/nrg2178","article-title":"Genome-wide association studies provide new insights into type 2 diabetes aetiology","volume":"8","author":"Frayling","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"2023012810451018600_btt308-B16","doi-asserted-by":"crossref","first-page":"e1001074","DOI":"10.1371\/journal.pgen.1001074","article-title":"Disease-associated mutations that alter the RNA structural ensemble","volume":"6","author":"Halvorsen","year":"2010","journal-title":"PLoS Genet."},{"key":"2023012810451018600_btt308-B17","doi-asserted-by":"crossref","first-page":"e1000752","DOI":"10.1371\/journal.pcbi.1000752","article-title":"Accurate distinction of pathogenic from benign CNVs in mental retardation","volume":"6","author":"Hehir-Kwa","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"2023012810451018600_btt308-B18","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1101\/gr.944903","article-title":"Selection on human genes as revealed by comparisons to chimpanzee cDNA","volume":"13","author":"Hellmann","year":"2003","journal-title":"Genome Res."},{"key":"2023012810451018600_btt308-B19","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1200\/JCO.2010.31.9327","article-title":"WT1 synonymous single nucleotide polymorphism rs16754 correlates with higher mRNA expression and predicts significantly improved outcome in favorable-risk pediatric acute myeloid leukemia: a report from the Children\u2019s Oncology Group","volume":"29","author":"Ho","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"2023012810451018600_btt308-B20","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/humu.9489","article-title":"Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation","volume":"28","author":"Khaddour","year":"2007","journal-title":"Hum. Mutat."},{"key":"2023012810451018600_btt308-B21","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1126\/science.1135308","article-title":"A \u201csilent\u201d polymorphism in the MDR1 gene changes substrate specificity","volume":"315","author":"Kimchi-Sarfaty","year":"2007","journal-title":"Science"},{"key":"2023012810451018600_btt308-B22","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0014-5793(99)01566-5","article-title":"Synonymous codon substitutions affect ribosome traffic and protein folding during in vitro translation","volume":"462","author":"Komar","year":"1999","journal-title":"FEBS Lett."},{"key":"2023012810451018600_btt308-B23","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1126\/science.1170160","article-title":"Coding-sequence determinants of gene expression in Escherichia coli","volume":"324","author":"Kudla","year":"2009","journal-title":"Science"},{"key":"2023012810451018600_btt308-B24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ajhg.2008.06.024","article-title":"Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data","volume":"83","author":"Li","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"2023012810451018600_btt308-B25","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1748-7188-6-26","article-title":"ViennaRNA Package 2.0","volume":"6","author":"Lorenz","year":"2011","journal-title":"Algorithms Mol. Biol."},{"key":"2023012810451018600_btt308-B26","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1056\/NEJMoa0908094","article-title":"Whole-genome sequencing in a patient with Charcot\u2013Marie\u2013Tooth neuropathy","volume":"362","author":"Lupski","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"2023012810451018600_btt308-B27","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1002\/humu.21546","article-title":"Mutations in NOTCH2 in families with Hajdu-Cheney syndrome","volume":"32","author":"Majewski","year":"2011","journal-title":"Hum. Mutat."},{"key":"2023012810451018600_btt308-B28","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1136\/jmedgenet-2011-100223","article-title":"What can exome sequencing do for you?","volume":"48","author":"Majewski","year":"2011","journal-title":"J. Med. Genet."},{"key":"2023012810451018600_btt308-B29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-60327-429-6_1","article-title":"UNAFold: Software for nucleic acid folding and hybridization","volume":"453","author":"Markham","year":"2008","journal-title":"Methods in Molecular Biology"},{"key":"2023012810451018600_btt308-B30","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1038\/351652a0","article-title":"Adaptive protein evolution at the Adh locus in Drosophila","volume":"351","author":"McDonald","year":"1991","journal-title":"Nature"},{"key":"2023012810451018600_btt308-B31","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.mrfmmm.2006.09.003","article-title":"A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: a cohort allelic sums test (CAST)","volume":"615","author":"Morgenthaler","year":"2007","journal-title":"Mutat. Res.\/Fundam. Mol. Mech. Mutagen."},{"key":"2023012810451018600_btt308-B32","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1093\/nar\/28.1.292","article-title":"Codon usage tabulated from international DNA sequence databases: status for the year 2000","volume":"28","author":"Nakamura","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2023012810451018600_btt308-B33","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2023012810451018600_btt308-B34","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/ng.499","article-title":"Exome sequencing identifies the cause of a mendelian disorder","volume":"42","author":"Ng","year":"2009","journal-title":"Nat. Genet."},{"key":"2023012810451018600_btt308-B35","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/ng.835","article-title":"Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations","volume":"43","author":"O\u2019Roak","year":"2011","journal-title":"Nat. Genet."},{"key":"2023012810451018600_btt308-B36","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/molbev\/msj035","article-title":"Evidence for purifying selection against synonymous mutations in mammalian exonic splicing enhancers","volume":"23","author":"Parmley","year":"2006","journal-title":"Mol. Biol. Evol."},{"key":"2023012810451018600_btt308-B37","doi-asserted-by":"crossref","first-page":"3894","DOI":"10.1093\/nar\/gkf493","article-title":"Human non-synonymous SNPs: server and survey","volume":"30","author":"Ramensky","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2023012810451018600_btt308-B38","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1038\/leu.2011.173","article-title":"Wilms\u2019 tumor 1 single-nucleotide polymorphism rs16754 does not predict clinical outcome in adult acute myeloid leukemia","volume":"25","author":"Renneville","year":"2011","journal-title":"Leukemia"},{"key":"2023012810451018600_btt308-B39","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1093\/nar\/gks1009","article-title":"Sensitive measurement of single-nucleotide polymorphism-induced changes of RNA conformation: application to disease studies","volume":"41","author":"Salari","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2023012810451018600_btt308-B40","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/nrg3051","article-title":"Understanding the contribution of synonymous mutations to human disease","volume":"12","author":"Sauna","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"2023012810451018600_btt308-B41","first-page":"743","article-title":"PyBrain","volume":"11","author":"Schaul","year":"2010","journal-title":"J. Mach. Learn. Res."},{"key":"2023012810451018600_btt308-B42","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1093\/nar\/15.3.1281","article-title":"The codon adaptation index\u2014a measure of directional synonymous codon usage bias, and its potential applications","volume":"15","author":"Sharp","year":"1987","journal-title":"Nucleic Acids Res."},{"key":"2023012810451018600_btt308-B43","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.1093\/hmg\/ddl171","article-title":"An increased specificity score matrix for the prediction of SF2\/ASF-specific exonic splicing enhancers","volume":"15","author":"Smith","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"2023012810451018600_btt308-B44","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1101\/gr.6023607","article-title":"Recent human effective population size estimated from linkage disequilibrium","volume":"17","author":"Tenesa","year":"2007","journal-title":"Genome Res."},{"key":"2023012810451018600_btt308-B45","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1101\/gr.772403","article-title":"PANTHER: a library of protein families and subfamilies indexed by function","volume":"13","author":"Thomas","year":"2003","journal-title":"Genome Res."},{"key":"2023012810451018600_btt308-B46","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1089\/cmb.2011.0181","article-title":"An unbiased adaptive sampling algorithm for the exploration of RNA mutational landscapes under evolutionary pressure","volume":"18","author":"Waldisp\u00fchl","year":"2011","journal-title":"Journal of Computational Biology"},{"key":"2023012810451018600_btt308-B47","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nature07999","article-title":"Common genetic variants on 5p14.1 associate with autism spectrum disorders","volume":"459","author":"Wang","year":"2009","journal-title":"Nature"},{"key":"2023012810451018600_btt308-B48","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.cell.2004.11.010","article-title":"Systematic identification and analysis of exonic splicing silencers","volume":"119","author":"Wang","year":"2004","journal-title":"Cell"},{"key":"2023012810451018600_btt308-B49","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1101\/gr.123158.111","article-title":"A probabilistic disease-gene finder for personal genomes","volume":"21","author":"Yandell","year":"2011","journal-title":"Genome Res."},{"key":"2023012810451018600_btt308-B50","doi-asserted-by":"crossref","first-page":"7323","DOI":"10.1128\/MCB.25.16.7323-7332.2005","article-title":"Exon inclusion is dependent on predictable exonic splicing enhancers","volume":"25","author":"Zhang","year":"2005","journal-title":"Mol. Cell. Biol."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/15\/1843\/48887752\/bioinformatics_29_15_1843.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/15\/1843\/48887752\/bioinformatics_29_15_1843.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T12:28:34Z","timestamp":1674908914000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/29\/15\/1843\/265132"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,4]]},"references-count":50,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2013,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btt308","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2013,8,1]]},"published":{"date-parts":[[2013,6,4]]}}}