{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T17:08:42Z","timestamp":1777828122802,"version":"3.51.4"},"reference-count":24,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R43HG012537"],"award-info":[{"award-number":["R43HG012537"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM121325"],"award-info":[{"award-number":["P20GM121325"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of the activity of 70 synonymous variants in the HIV Tat transcription factor revealed that 50% of the variants exhibited significant deviations from wild-type activity. Our analysis supports previous work and raises important questions about the broader impact of non-silent synonymous variants in human genes. Considering the potential functional implications, the authors propose classifying such variants as \u201csynonymous variants of uncertain silence\u201d (sVUS), highlighting the need for cautious interpretation and further investigations in clinical and genetic testing settings.<\/jats:p>","DOI":"10.3390\/ijms241310556","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T01:42:32Z","timestamp":1687743752000},"page":"10556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synonymous Variants of Uncertain Silence"],"prefix":"10.3390","volume":"24","author":[{"given":"Christopher J.","family":"Giacoletto","sequence":"first","affiliation":[{"name":"Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA"},{"name":"Heligenics Inc., 10530 Discovery Drive, Las Vegas, NV 89135, USA"},{"name":"School of Life Sciences, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7191-1723","authenticated-orcid":false,"given":"Jerome I.","family":"Rotter","sequence":"additional","affiliation":[{"name":"Heligenics Inc., 10530 Discovery Drive, Las Vegas, NV 89135, USA"},{"name":"The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne W.","family":"Grody","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California Los Angeles School of Medicine, 10833 Le Conte Ave., 705, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, University of California Los Angeles School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095, USA"},{"name":"Department of Human Genetics, University of California Los Angeles School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1671-6823","authenticated-orcid":false,"given":"Martin R.","family":"Schiller","sequence":"additional","affiliation":[{"name":"Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA"},{"name":"Heligenics Inc., 10530 Discovery Drive, Las Vegas, NV 89135, USA"},{"name":"School of Life Sciences, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1073\/pnas.47.10.1588","article-title":"The Dependence of Cell-Free Protein Synthesis in E. coli upon Naturally Occurring or Synthetic Polyribonucleotides","volume":"47","author":"Nirenberg","year":"1961","journal-title":"Proc. Natl. Acad. Sci. 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