{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T18:47:11Z","timestamp":1767034031951,"version":"3.41.2"},"reference-count":21,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T00:00:00Z","timestamp":1586908800000},"content-version":"vor","delay-in-days":105,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["388217"],"award-info":[{"award-number":["388217"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003243","name":"Ministry of Health of the Czech Republic","doi-asserted-by":"publisher","award":["16-30206"],"award-info":[{"award-number":["16-30206"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Genetic variation occurring within conserved functional protein domains warrants special attention when examining DNA variation in the context of disease causation. Here we introduce a resource, freely available at www.prot2hg.com, that addresses the question of whether a particular variant falls onto an annotated protein domain and directly translates chromosomal coordinates onto protein residues. The tool can perform a multiple-site query in a simple way, and the whole dataset is available for download as well as incorporated into our own accessible pipeline. To create this resource, National Center for Biotechnology Information protein data were retrieved using the Entrez Programming Utilities. After processing all human protein domains, residue positions were reverse translated and mapped to the reference genome hg19 and stored in a MySQL database. In total, 760\u2009487 protein domains from 42\u2009371 protein models were mapped to hg19 coordinates and made publicly available for search or download (www.prot2hg.com). In addition, this annotation was implemented into the genomics research platform GENESIS in order to query nearly 8000 exomes and genomes of families with rare Mendelian disorders (tgp-foundation.org). When applied to patient genetic data, we found that rare (&amp;lt;1%) variants in the Genome Aggregation Database were significantly more annotated onto a protein domain in comparison to common (&amp;gt;1%) variants. Similarly, variants described as pathogenic or likely pathogenic in ClinVar were more likely to be annotated onto a domain. In addition, we tested a dataset consisting of 60 causal variants in a cohort of patients with epileptic encephalopathy and found that 71% of them (43 variants) were propagated onto protein domains. In summary, we developed a resource that annotates variants in the coding part of the genome onto conserved protein domains in order to increase variant prioritization efficiency.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Database URL: www.prot2hg.com<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/database\/baz161","type":"journal-article","created":{"date-parts":[[2020,1,2]],"date-time":"2020-01-02T12:08:05Z","timestamp":1577966885000},"source":"Crossref","is-referenced-by-count":17,"title":["Prot2HG: a database of protein domains mapped to the human genome"],"prefix":"10.1093","volume":"2020","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2583-2562","authenticated-orcid":false,"given":"David","family":"Stanek","sequence":"first","affiliation":[{"name":"DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, V \u00davalu 84, 150 06 Czech Republic"}]},{"given":"Dana M","family":"Bis-Brewer","sequence":"first","affiliation":[{"name":"Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}]},{"given":"Cima","family":"Saghira","sequence":"first","affiliation":[{"name":"Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}]},{"given":"Matt C","family":"Danzi","sequence":"first","affiliation":[{"name":"Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}]},{"given":"Pavel","family":"Seeman","sequence":"first","affiliation":[{"name":"DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, V \u00davalu 84, 150 06 Czech Republic"}]},{"given":"Petra","family":"Lassuthova","sequence":"first","affiliation":[{"name":"DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, V \u00davalu 84, 150 06 Czech Republic"}]},{"given":"Stephan","family":"Zuchner","sequence":"first","affiliation":[{"name":"Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}]}],"member":"286","published-online":{"date-parts":[[2020,4,15]]},"reference":[{"key":"2020041504454189700_ref1","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":"2020041504454189700_ref2","doi-asserted-by":"crossref","DOI":"10.15252\/emmm.201910486","article-title":"International collaborative actions and transparency to understand, diagnose, and develop therapies for rare diseases","volume":"11","author":"Boycott","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"2020041504454189700_ref3","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2020041504454189700_ref4","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1101\/gr.3715005","article-title":"Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes","volume":"15","author":"Siepel","year":"2005","journal-title":"Genome Res."},{"key":"2020041504454189700_ref5","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2020041504454189700_ref6","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":"2020041504454189700_ref7","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."},{"year":"2002","author":"Sayers","key":"2020041504454189700_ref8"},{"key":"2020041504454189700_ref9","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1093\/bioinformatics\/btw547","article-title":"Integrating genomic information with protein sequence and 3D atomic level structure at the RCSB protein data bank","volume":"32","author":"Prlic","year":"2016","journal-title":"Bioinformatics"},{"key":"2020041504454189700_ref10","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2019","journal-title":"Genome Biol."},{"key":"2020041504454189700_ref11","doi-asserted-by":"crossref","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","article-title":"Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation","volume":"44","author":"O\u2019Leary","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2020041504454189700_ref12","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1146\/annurev.bi.64.070195.001443","article-title":"The multiplicity of domains in proteins","volume":"64","author":"Doolittle","year":"1995","journal-title":"Annu. Rev. Biochem."},{"author":"Sayers","key":"2020041504454189700_ref13"},{"key":"2020041504454189700_ref14","article-title":"The biological code","volume":"12","author":"Ycas","year":"1969","journal-title":"Frontiers of Biology."},{"key":"2020041504454189700_ref15","first-page":"733","article-title":"IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN) and Nomenclature Committee of IUBMB (NC-IUBMB). Newsletter 1996","volume":"247","author":"Liebecq","year":"1997","journal-title":"Eur. J. Biochem."},{"key":"2020041504454189700_ref16","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":"2020041504454189700_ref17","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2020041504454189700_ref18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13023-018-0812-8","article-title":"Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life","volume":"13","author":"Stanek","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"2020041504454189700_ref19","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13073-017-0412-6","article-title":"Lessons learned from additional research analyses of unsolved clinical exome cases","volume":"9","author":"Eldomery","year":"2017","journal-title":"Genome Med."},{"key":"2020041504454189700_ref20","doi-asserted-by":"crossref","first-page":"958","DOI":"10.3389\/fneur.2018.00958","article-title":"Perspectives on the genomics of HSP beyond Mendelian inheritance","volume":"9","author":"Bis-Brewer","year":"2018","journal-title":"Front. Neurol"},{"key":"2020041504454189700_ref21","doi-asserted-by":"crossref","first-page":"D1018","DOI":"10.1093\/nar\/gky1105","article-title":"Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources","volume":"47","author":"Kohler","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["Database"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/database\/article-pdf\/doi\/10.1093\/database\/baz161\/33045008\/baz161.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/database\/article-pdf\/doi\/10.1093\/database\/baz161\/33045008\/baz161.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T08:46:15Z","timestamp":1586940375000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/database\/article\/doi\/10.1093\/database\/baz161\/5820062"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":21,"URL":"https:\/\/doi.org\/10.1093\/database\/baz161","relation":{},"ISSN":["1758-0463"],"issn-type":[{"type":"electronic","value":"1758-0463"}],"subject":[],"published-other":{"date-parts":[[2020]]},"published":{"date-parts":[[2020,1,1]]},"article-number":"baz161"}}