rs1555687377
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005359.6(SMAD4):c.1309-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005359.6 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.1309-1G>A | splice_acceptor_variant, intron_variant | Intron 10 of 11 | ENST00000342988.8 | NP_005350.1 | ||
SMAD4 | NM_001407041.1 | c.1309-1G>A | splice_acceptor_variant, intron_variant | Intron 10 of 11 | NP_001393970.1 | |||
SMAD4 | NM_001407042.1 | c.1309-1G>A | splice_acceptor_variant, intron_variant | Intron 10 of 11 | NP_001393971.1 | |||
SMAD4 | NR_176265.1 | n.1847-1G>A | splice_acceptor_variant, intron_variant | Intron 10 of 12 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The c.1309-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 10 of the SMAD4 gene. In addition, alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). Based on the available evidence, c.1309-1G>A is classified as a pathogenic mutation. -
Juvenile polyposis syndrome Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change affects an acceptor splice site in intron 10 of the SMAD4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD4-related disease. 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at