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Among the <jats:italic>GREB1L<\/jats:italic> variants reported, most of them are missense or frameshift, while no pathogenic synonymous variants have been recorded. Classical theory paid little attention to synonymous variants and classified it as nonpathogenic; however, recent studies suggest that the variants might be equally important. Here, we report a 7\u2010year\u2010old girl with new symptoms of clitoromegaly, uterovaginal, and ovarian agenesis as well as right kidney missing. A novel <jats:italic>de novo<\/jats:italic> <jats:italic>GREB1L<\/jats:italic> synonymous variant (NM_001142966: c.4731C&gt;T, p.G1577=) was identified via whole exome sequencing. The variant was predicted to be disease\u2010causing through <jats:italic>in silico<\/jats:italic> analysis and was classified as likely pathogenic. Minigene splicing assays confirmed a 6\u2009bp deletion in mutant cDNA comparing with the wild type, leading to two amino acids lost in GREB1L protein. Secondary and tertiary structure modeling showed alterations in protein structure. Our finding reveals a novel <jats:italic>GREB1L<\/jats:italic> variant with a new phenotype of urogenital system and is the first to report a pathogenic synonymous variant in <jats:italic>GREB1L<\/jats:italic> which affects mRNA splicing, suggesting synonymous variants cannot be ignored in prenatal diagnosis and genetic counseling.<\/jats:p>","DOI":"10.1002\/ajmg.a.63823","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T03:07:35Z","timestamp":1722568055000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel <i>de novo<\/i> synonymous variant in <scp><i>GREB1L<\/i><\/scp> impacts the <scp>mRNA<\/scp> splicing associated with aplasia of the urogenital system"],"prefix":"10.1002","volume":"194","author":[{"given":"Yaoping","family":"Wang","sequence":"first","affiliation":[{"name":"Medical Genetic Institute of Henan Province Zhengzhou University People's Hospital, Henan Provincial People's Hospital  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6498-9979","authenticated-orcid":false,"given":"Hongdan","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical Genetic Institute of Henan Province Zhengzhou University People's Hospital, Henan Provincial People's Hospital  Zhengzhou China"},{"name":"National Health Commission Key Laboratory of Birth Defects Prevention Henan Key Laboratory of Population Defects Prevention  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenke","family":"Yang","sequence":"additional","affiliation":[{"name":"Medical Genetic Institute of Henan Province Zhengzhou University People's Hospital, Henan Provincial People's Hospital  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Huadong Hospital, Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Medical Genetic Institute of Henan Province Zhengzhou University People's Hospital, Henan Provincial People's Hospital  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Gao","sequence":"additional","affiliation":[{"name":"Medical Genetic Institute of Henan Province Zhengzhou University People's Hospital, Henan Provincial People's Hospital  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Kang","sequence":"additional","affiliation":[{"name":"Medical Genetic Institute of Henan Province Zhengzhou University People's Hospital, Henan Provincial People's Hospital  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shixiu","family":"Liao","sequence":"additional","affiliation":[{"name":"Medical Genetic Institute of Henan Province Zhengzhou University People's Hospital, Henan Provincial People's Hospital  Zhengzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.173"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.117.1125"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.110601"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11195598"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1770"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-022-00385-0"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.09.026"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11596-021-2436-9"},{"issue":"22","key":"e_1_2_9_10_1","first-page":"6367","article-title":"PDZK1 and GREB1 are estrogen\u2010regulated genes expressed in hormone\u2010responsive breast cancer","volume":"60","author":"Ghosh M. 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