rs377767386
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_005359.6(SMAD4):c.424+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005359.6 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.424+1G>A | splice_donor_variant | ENST00000342988.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.424+1G>A | splice_donor_variant | 5 | NM_005359.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457654Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 725262
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Juvenile polyposis syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 07, 2023 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1738995). This variant is also known as +1 splice donor intron 2 g > a. Disruption of this splice site has been observed in individual(s) with juvenile polyposis syndrome (PMID: 11583957). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the SMAD4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2020 | The c.424+1G>A variant in SMAD4 has been reported in 1 individual with juvenile polyposis syndrome and segregated with disease in at least 2 affected family members (Woodford-Richens 2001). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the SMAD4 gene is an established disease mechanism in autosomal dominant juvenile polyposis syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant juvenile polyposis syndrome. ACMG/AMP criteria applied: PVS1_Strong, PM2, PP4. - |
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2017 | The c.424+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the SMAD4 gene. This mutation was previously identified in a family affected with juvenile polyposis syndrome (Woodford-Richens KL et al. Am. J. Pathol., 2001 Oct;159:1293-300). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at