ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.2001+4A>G

dbSNP: rs1343722342
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564298 SCV000664196 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-14 criteria provided, single submitter clinical testing The c.2001+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 12 in the SMARCA4 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 30000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in mammals. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000694315 SCV000822753 uncertain significance Rhabdoid tumor predisposition syndrome 2 2018-06-07 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the SMARCA4 gene. It does not directly change the encoded amino acid sequence of the SMARCA4 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related disease. ClinVar contains an entry for this variant (Variation ID: 480621). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab RCV001809585 SCV002056478 uncertain significance Intellectual disability, autosomal dominant 16 2021-07-15 criteria provided, single submitter clinical testing

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