ArticleHuman mutation2020
AG-exclusion zone revisited: Lessons to learn from 91 intronic NF1 3' splice site mutations outside the canonical AG-dinucleotides.
Article in Human mutation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- The Tyrolean FounderBiomolecules · 2026Article
- Functional validation of spliceogenic COL4A3 and COL4A4 variants by minigene assays refines molecular diagnosis of Alport syndrome.Human genomics · 2026Article
- Genetic characterization of a Chinese cohort of suspected pediatric NF1 patients: a large-scale study using optimized whole-exome sequencing.Journal of human genetics · 2026Article
- Whole-genome sequencing in Brazilian patients with neurofibromatosis type 1, including novel variants, incidental findings, and dual diagnoses.Einstein (Sao Paulo, Brazil) · 2026Article
- Data-driven insights to inform splice-altering variant assessment.American journal of human genetics · 2025Article
- Splicing accuracy varies across human introns, tissues, age and disease.Nature communications · 2025Article
- A deep intronic mutation causes RAD50 deficiency through an unusual mechanism of distant exon activation.The Journal of clinical investigation · 2024Article
- RNA variant assessment using transactivation and transdifferentiation.American journal of human genetics · 2024Article
- A Comprehensive Overview of NF1 Mutations in Iranian Patients.Neuromolecular medicine · 2024Article
- Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Article
- High-yield identification of pathogenic NF1 variants by skin fibroblast transcriptome screening after apparently normal diagnostic DNA testing.Human mutation · 2022Article
- Combining genetic constraint with predictions of alternative splicing to prioritize deleterious splicing in rare disease studies.BMC bioinformatics · 2022Article
- Genome-wide detection of human variants that disrupt intronic branchpoints.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Prevalence, parameters, and pathogenic mechanisms for splice-altering acceptor variants that disrupt the AG exclusion zone.HGG advances · 2022Article
- Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study.Cancer research and treatment · 2022Article
- Genotype-Phenotype Correlations in Neurofibromatosis Type 1: Identification of Novel and RecurrentGenes · 2022Article
- Mutation analysis reveals novel and known mutations in SAG gene in first two Egyptian families with Oguchi disease.BMC ophthalmology · 2022Article
- Identification of an elusive spliceogenic MYBPC3 variant in an otherwise genotype-negative hypertrophic cardiomyopathy pedigree.Scientific reports · 2022Article
- Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.Human mutation · 2022Article
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10 authors.
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Abstract
Uncovering frequent motives of action by which variants impair 3' splice site (3'ss) recognition and selection is essential to improve our understanding of this complex process. Through several mini-gene experiments, we demonstrate that the pyrimidine (Y) to purine (R) transversion NM_000267.3(NF1):c.1722-11T>G, although expected to weaken the polypyrimidine tract, causes exon skipping primarily by introducing a novel AG in the AG-exclusion zone (AGEZ) between the authentic 3'ss AG and the branch point. Evaluation of 90 additional noncanonical intronic NF1 3'ss mutations confirmed that 63% of all mutations and 89% (49/55) of the single-nucleotide variants upstream of positions -3 interrupt the AGEZ. Of these AGEZ-interrupting mutations, 24/49 lead to exon skipping suggesting that absence of AG in this region is necessary for accurate 3'ss selection already in the initial steps of splicing. The analysis of 91 noncanonical NF1 3'ss mutations also shows that 90% either introduce a novel AG in the AGEZ, cause a Y>R transversion at position -3 or remove ≥2 Ys in the AGEZ. We confirm in a validation cohort that these three motives distinguish spliceogenic from splice-neutral variants with 85% accuracy and, therefore, are generally applicable to select among variants of unknown significance those likely to affect splicing.
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