chr18-51048726-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_005359.6(SMAD4):c.290G>T(p.Arg97Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97C) has been classified as Uncertain significance.
Frequency
Consequence
NM_005359.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.290G>T | p.Arg97Leu | missense_variant | 3/12 | ENST00000342988.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.290G>T | p.Arg97Leu | 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
Heritable Thoracic Aortic Disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Department of Internal Medicine, The University of Texas McGovern Medical School, The University of Texas Health Science Center at Houston | Apr 01, 2018 | This variant was identified in a family with thoracic aortic disease and no evidence of juvenile polyposis and/or hereditary hemorrhagic telangiectasia - |
Heritable thoracic aortic disease without juvenile polyposis and hereditary hemorrhagic telangiectasia Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Juvenile polyposis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2020 | 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. This variant has been reported to affect SMAD4 protein function (PMID: 30809044). This variant has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 30809044). ClinVar contains an entry for this variant (Variation ID: 560163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 97 of the SMAD4 protein (p.Arg97Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at