ArticleGenome research2019
Pathogenicity and selective constraint on variation near splice sites.
Article in Genome research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A systematic review and meta-analysis of GFAP gene variants in Alexander disease.Scientific reports · 2024Pooled it
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.Nature communications · 2026Article
- AAVC: An automated framework for high-accuracy ACMG-based variant classification.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden.Journal of translational medicine · 2026Article
- Targeted reflex RNA sequencing for enhanced variant classification on exome and genome sequencing improves patient outcomes.NPJ genomic medicine · 2026Article
- Functional analysis of AIP variants in a cohort of neuroendocrine neoplasms.Endocrine-related cancer · 2026Article
- Cell modeling and rescue of a novel noncoding genetic cause of glycogen storage disease IX.Genetics in medicine open · 2026Article
- Clinical Variant Databases and Machine Learning Prediction Supporting Genomic Medicine.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.bioRxiv : the preprint server for biology · 2025Article
- A systematic analysis of contemporary whole exome sequencing capture kits to optimise high-coverage capture of CCDS regions.NAR genomics and bioinformatics · 2025Article
- Early diagnosed Zaki syndrome: identification of two novel WLS variants and a literature review.Italian journal of pediatrics · 2025Review
- Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay.Molecular psychiatry · 2025Article
- Identifying deleterious noncoding variation through gain and loss of CTCF binding activity.American journal of human genetics · 2025Article
- Assessing Splicing Variants in the PAX6 Gene: A Comprehensive Minigene Approach.Journal of cellular and molecular medicine · 2025Article
- Predicting the impact of rare variants on RNA splicing in CAGI6.Human genetics · 2025Article
- Case Report: Functional validation of a rare variantFrontiers in oncology · 2025Article
- A novel homozygous intronic variant in CDT1 that alters splicing causes Meier-Gorlin syndrome, and a review of published mutations and growth hormone treatments.Orphanet journal of rare diseases · 2024Review
- Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Validating the splicing effect of rare variants in the SLC26A4 gene using minigene assay.BMC medical genomics · 2024Article
- Context-adjusted proportion of singletons (CAPS): a novel metric for assessing negative selection in the human genome.NAR genomics and bioinformatics · 2024Article
Corrections and comments
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Authors and funding
29 authors.
Funding
Abstract
Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.