{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T13:18:36Z","timestamp":1770902316183,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto Nacional de Pediatr\u00eda, Secretar\u00eda de Salud"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: ASXL1 is a chromatin-associated gene implicated in both hematologic malignancies and neurodevelopmental disorders, including Bohring\u2013Opitz syndrome (BOS). Although many ASXL1 variants are well classified, a substantial proportion remain variants of uncertain significance (VUS), complicating molecular diagnosis and genetic counseling. The objective of this study was to evaluate whether structural context can inform the interpretation of selected ASXL1 missense variants in a clinical setting. Methods: We describe a 17-year-old female with clinical features consistent with BOS carrying the heterozygous ASXL1 variant p.Q1448R, currently classified as benign under ACMG\/AMP guidelines. Three-dimensional in silico structural modeling was performed using AlphaFold3 and available crystallographic data. Three additional ASXL1 missense variants classified as VUS in ClinVar (p.R265H, p.T297M, and p.Y358C) were also analyzed. Evolutionary conservation, domain localization, and residue-level interactions were assessed. Results: Structural modeling indicated that the p.Q1448R substitution alters polar interactions and introduces a steric constraint near a conserved PHD-type zinc finger domain. Variants p.R265H and p.T297M affected stabilizing interactions within the DEUBAD, which is involved in BAP1 activation, while p.Y358C altered a polar microenvironment adjacent to a chromatin-interacting region. All analyzed variants, except p.T297M, localized to evolutionarily conserved regions. Conclusions: This study demonstrates that in silico structural analysis can provide complementary, domain-level insights for the interpretation of ASXL1 missense variants that remain classified as benign, likely benign or VUS under current frameworks. Such approaches may assist in prioritizing variants for further functional evaluation and refining molecular interpretation when experimental data are limited.<\/jats:p>","DOI":"10.3390\/genes17020231","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:05:46Z","timestamp":1770897946000},"page":"231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reassessing Benign ASXL1 Variants in Bohring\u2013Opitz Syndrome: The Role of Population Databases in Variant Reinterpretation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-6966","authenticated-orcid":false,"given":"Liliana","family":"Fern\u00e1ndez-Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular, Instituto Nacional de Pediatr\u00eda, Secretar\u00eda de Salud, Mexico City C.P. 04530, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2058-5707","authenticated-orcid":false,"given":"Sergio","family":"Enr\u00edquez-Flores","sequence":"additional","affiliation":[{"name":"Laboratorio de Biomol\u00e9culas y Salud Infantil, Instituto Nacional de Pediatr\u00eda, Secretar\u00eda de Salud, Mexico City C.P. 04530, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy L.","family":"Hern\u00e1ndez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular, Instituto Nacional de Pediatr\u00eda, Secretar\u00eda de Salud, Mexico City C.P. 04530, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8591-0852","authenticated-orcid":false,"given":"Melania","family":"Abreu-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Laboratorio Genos M\u00e9dica, Mexico City C.P.06700, Mexico"},{"name":"Centro M\u00e9dico ABC, Mexico City C.P. 05300, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Lieberman-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica Humana, Instituto Nacional de Pediatr\u00eda, Secretar\u00eda de Salud, Mexico City C.P. 04530, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerardo","family":"Rodr\u00edguez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Subdirecci\u00f3n de Servicios Cl\u00ednicos, Gen\u00e9tica, Hospital Regional de Alta Especialidad de Zumpango, Zumpango C.P. 55600, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinuh\u00e9","family":"Reyes-Ruvalcaba","sequence":"additional","affiliation":[{"name":"Universidad Cuauht\u00e9moc, Campus Quer\u00e9taro, Quer\u00e9taro C.P. 76060, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam E.","family":"Reyna-Fabi\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular, Instituto Nacional de Pediatr\u00eda, Secretar\u00eda de Salud, Mexico City C.P. 04530, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"ref_1","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":"ref_2","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.ajhg.2016.03.024","article-title":"Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium","volume":"98","author":"Amendola","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/gim.2017.37","article-title":"Sherloc: A Comprehensive Refinement of the ACMG-AMP Variant Classification Criteria","volume":"19","author":"Nykamp","year":"2017","journal-title":"Genet. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1002\/humu.24088","article-title":"Fitting a Naturally Scaled Point System to the ACMG\/AMP Variant Classification Guidelines","volume":"41","author":"Tavtigian","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/gim.2017.210","article-title":"Modeling the ACMG\/AMP Variant Classification Guidelines as a Bayesian Classification Framework","volume":"20","author":"Tavtigian","year":"2018","journal-title":"Genet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1038\/s41436-021-01254-2","article-title":"Disease-Specific ACMG\/AMP Guidelines Improve Sequence Variant Interpretation for Hearing Loss","volume":"23","author":"Patel","year":"2021","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12967-022-03251-8","article-title":"Good Performance of the Criteria of American College of Medical Genetics and Genomics\/Association for Molecular Pathology in Prediction of Pathogenicity of Genetic Variants Causing Thoracic Aortic Aneurysms and Dissections","volume":"20","author":"Truszkowska","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_8","unstructured":"(2026, January 13). GnomAD. Available online: https:\/\/gnomad.broadinstitute.org\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A Genomic Mutational Constraint Map Using Variation in 76,156 Human Genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/s41586-020-2819-2","article-title":"Inherited Causes of Clonal Haematopoiesis in 97,691 Whole Genomes","volume":"586","author":"Bick","year":"2020","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00439-023-02526-4","article-title":"Interpreting Variants in Genes Affected by Clonal Hematopoiesis in Population Data","volume":"143","author":"Gudmundsson","year":"2024","journal-title":"Hum. Genet."},{"key":"ref_12","first-page":"1606","article-title":"Clonal Hematopoiesis and Non-Hematologic Disorders","volume":"136","author":"Jaiswal","year":"2020","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/humu.23203","article-title":"Pathogenic ASXL1 Somatic Variants in Reference Databases Complicate Germline Variant Interpretation for Bohring\u2013Opitz Syndrome","volume":"38","author":"Carlston","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/humu.23217","article-title":"Bad Blood Contaminating Germline Databases?","volume":"38","author":"Churpek","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10292","DOI":"10.1038\/ncomms10292","article-title":"BAP1\/ASXL1 Recruitment and Activation for H2A Deubiquitination","volume":"7","author":"Sahtoe","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nature08966","article-title":"Histone H2A Deubiquitinase Activity of the Polycomb Repressive Complex PR-DUB","volume":"465","author":"Scheuermann","year":"2010","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eadg9832","DOI":"10.1126\/sciadv.adg9832","article-title":"Structural Basis of Histone H2A Lysine 119 Deubiquitination by Polycomb Repressive Deubiquitinase BAP1\/ASXL1","volume":"9","author":"Thomas","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_18","first-page":"364","article-title":"The PHD Finger: A Versatile Epigenome Reader","volume":"36","author":"Sanchez","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1186\/s13059-022-02776-x","article-title":"MBD5 and MBD6 Stabilize the BAP1 Complex and Promote BAP1-Dependent Cancer","volume":"23","author":"Tsuboyama","year":"2022","journal-title":"Genome Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1756-8722-5-12","article-title":"Mutations in ASXL1 Are Associated with Poor Prognosis across the Spectrum of Malignant Myeloid Diseases","volume":"5","author":"Brecqueville","year":"2012","journal-title":"J. Hematol. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/ng.868","article-title":"De Novo Nonsense Mutations in ASXL1 Cause Bohring-Opitz Syndrome","volume":"43","author":"Hoischen","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/ejhg.2010.234","article-title":"Bohring-Opitz (Oberklaid-Danks) Syndrome: Clinical Study, Review of the Literature, and Discussion of Possible Pathogenesis","volume":"19","author":"Hastings","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_23","unstructured":"(2026, January 13). \u201cASXL1\u201d[GENE]-ClinVar-NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/?term=%22ASXL1%22%5BGENE%5D&redir=gene."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and Accurate Short Read Alignment with Burrows-Wheeler Transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce Framework for Analyzing next-Generation DNA Sequencing Data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A Program for Annotating and Predicting the Effects of Single Nucleotide Polymorphisms, SnpEff: SNPs in the Genome of Drosophila Melanogaster Strain W1118; Iso-2; Iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"btac830","DOI":"10.1093\/bioinformatics\/btac830","article-title":"Igv.Js: An Embeddable JavaScript Implementation of the Integrative Genomics Viewer (IGV)","volume":"39","author":"Robinson","year":"2023","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1002\/humu.24309","article-title":"Variant Interpretation Using Population Databases: Lessons from GnomAD","volume":"43","author":"Gudmundsson","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein Structure Prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate Structure Prediction of Biomolecular Interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"107419","DOI":"10.1016\/j.leukres.2023.107419","article-title":"How Low Can You Go?: Methodologic Considerations in Clonal Hematopoiesis Variant Calling","volume":"135","author":"Beeler","year":"2023","journal-title":"Leuk. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Tabet, D.R., Cot\u00e9, A.G., Lancaster, M.C., Weile, J., Rayhan, A., Fotiadou, I., Kishore, N., Li, R., Kuang, D., and Knapp, J.J. (2025). The Functional Landscape of Coding Variation in the Familial Hypercholesterolemia Gene LDLR. Science, eady7186.","DOI":"10.1126\/science.ady7186"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1016\/j.ajhg.2025.08.019","article-title":"Landscapes of Missense Variant Impact for Human Superoxide Dismutase 1","volume":"112","author":"Axakova","year":"2025","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/cncr.32566","article-title":"Impact of the Variant Allele Frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the Outcomes of Patients with Newly Diagnosed Acute Myeloid Leukemia","volume":"126","author":"Sasaki","year":"2020","journal-title":"Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17588","DOI":"10.1074\/jbc.M512616200","article-title":"Additional Sex Comb-like 1 (ASXL1), in Cooperation with SRC-1, Acts as a Ligand-Dependent Coactivator for Retinoic Acid Receptor","volume":"281","author":"Cho","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7589","DOI":"10.1073\/pnas.0402191101","article-title":"Reduction in DNA-Binding Affinity of Cys 2 His 2 Zinc Finger Proteins by Linker Phosphorylation","volume":"101","author":"Jantz","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"McEwen, A.E., Stone, J., Tejura, M., Gupta, P., Capodanno, B.J., Da, E.Y., Grindstaff, S.B., Moore, N., Reinhart, D., and Snyder, A.E. (2025). MaveMD: A functional data resource for genomic medicine. medRxiv, medRxiv:2025.11.15.25336228.","DOI":"10.1101\/2025.11.15.25336228"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D1355","DOI":"10.1093\/nar\/gkaf1102","article-title":"ClinMAVE: A Curated Database for Clinical Application of Data from Multiplexed Assays of Variant Effect","volume":"54","author":"Ma","year":"2025","journal-title":"Nucleic Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/231\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:24:13Z","timestamp":1770899053000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/2\/231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["genes17020231"],"URL":"https:\/\/doi.org\/10.3390\/genes17020231","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,12]]}}}