ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.1139+3A>G

dbSNP: rs786202607
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002311027 SCV000216231 uncertain significance Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2019-01-03 criteria provided, single submitter clinical testing The c.1139+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 8 in the SMAD4 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been observed in at least one individual who has a personal or family history that is consistent with SMAD4-associated disease (Ambry internal data). Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001052725 SCV001216949 uncertain significance Juvenile polyposis syndrome 2019-02-15 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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. 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. This variant has not been reported in the literature in individuals with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 185983). This sequence change falls in intron 9 of the SMAD4 gene. It does not directly change the encoded amino acid sequence of the SMAD4 protein, but it affects a nucleotide within the consensus splice site of the intron.

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