{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T05:55:13Z","timestamp":1792130113307,"version":"4.4.0"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"44","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:p>\n                    Pre-messenger RNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Forty-eight rare variants in 43 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach was available to efficiently detect such variants in massively parallel sequencing data. We established a comprehensive human genome-wide BP database by integrating existing BP data and generating new BP data from RNA sequencing of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We characterized multiple features of BP in major and minor introns and found that BP and BP-2 (two nucleotides upstream of BP) positions exhibit a lower rate of variation in human populations and higher evolutionary conservation than the intronic background, while being comparable to the exonic background. We developed BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition. BPHunter retrospectively identified 40 of the 48 known pathogenic BP variants, in which we summarized a strategy for prioritizing BP variant candidates. The remaining eight variants all create AG-dinucleotides between the BP and acceptor site, which is the likely reason for missplicing. We demonstrated the practical utility of BPHunter prospectively by using it to identify a novel germline heterozygous BP variant of\n                    <jats:italic>STAT2<\/jats:italic>\n                    in a patient with critical COVID-19 pneumonia and a novel somatic intronic 59-nucleotide deletion of\n                    <jats:italic>ITPKB<\/jats:italic>\n                    in a lymphoma patient, both of which were validated experimentally. BPHunter is publicly available from\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/hgidsoft.rockefeller.edu\/BPHunter\">https:\/\/hgidsoft.rockefeller.edu\/BPHunter<\/jats:ext-link>\n                    and\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/casanova-lab\/BPHunter\">https:\/\/github.com\/casanova-lab\/BPHunter<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1073\/pnas.2211194119","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T13:34:16Z","timestamp":1666964056000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":47,"title":["Genome-wide detection of human variants that disrupt intronic branchpoints"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6129-567X","authenticated-orcid":false,"given":"Peng","family":"Zhang","sequence":"first","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Philippot","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France"},{"name":"Paris Cit\u00e9 University, Imagine Institute, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weicheng","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Te","family":"Lei","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Stenson","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pere Soler","family":"Palac\u00edn","sequence":"additional","affiliation":[{"name":"Infection in Immunocompromised Pediatric Patients Research Group, Vall d\u2019Hebron Research Institute, Vall d\u2019Hebron Barcelona Hospital Campus, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Research Institute, Vall d\u2019Hebron Barcelona Hospital Campus, Autonomous University of Barcelona, 08035 Barcelona, Spain"},{"name":"Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Colobran","sequence":"additional","affiliation":[{"name":"Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, 08035 Barcelona, Spain"},{"name":"Diagnostic Immunology Group, Vall d\u2019Hebron Research Institute, Vall d\u2019Hebron Barcelona Hospital Campus, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Immunology Division, Genetics Department, Vall d\u2019Hebron University Hospital, Vall d\u2019Hebron Barcelona Hospital Campus, Autonomous University of Barcelona, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5240-3555","authenticated-orcid":false,"given":"Bertrand","family":"Boisson","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065"},{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France"},{"name":"Paris Cit\u00e9 University, Imagine Institute, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen-Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065"},{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France"},{"name":"Paris Cit\u00e9 University, Imagine Institute, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2603-0323","authenticated-orcid":false,"given":"Anne","family":"Puel","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065"},{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France"},{"name":"Paris Cit\u00e9 University, Imagine Institute, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Pan-Hammarstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065"},{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France"},{"name":"Paris Cit\u00e9 University, Imagine Institute, 75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8943-8484","authenticated-orcid":false,"given":"David N.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Abel","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, 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