chr18-51048726-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_005359.6(SMAD4):c.290G>A(p.Arg97His) variant causes a missense 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005359.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.290G>A | p.Arg97His | missense_variant | 3/12 | ENST00000342988.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.290G>A | p.Arg97His | missense_variant | 3/12 | 5 | NM_005359.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2019 | The p.R97H variant (also known as c.290G>A), located in coding exon 2 of the SMAD4 gene, results from a G to A substitution at nucleotide position 290. The arginine at codon 97 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Juvenile polyposis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 11, 2021 | This sequence change replaces arginine with histidine at codon 97 of the SMAD4 protein (p.Arg97His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SMAD4-related disease. This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at