18-51054973-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_005359.6(SMAD4):āc.647A>Gā(p.Asn216Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005359.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.647A>G | p.Asn216Ser | missense_variant | Exon 5 of 12 | ENST00000342988.8 | NP_005350.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.647A>G | p.Asn216Ser | missense_variant | Exon 5 of 12 | 5 | NM_005359.6 | ENSP00000341551.3 | ||
ENSG00000267699 | ENST00000590722.2 | n.*823A>G | non_coding_transcript_exon_variant | Exon 8 of 9 | 2 | ENSP00000465737.1 | ||||
ENSG00000267699 | ENST00000590722.2 | n.*823A>G | 3_prime_UTR_variant | Exon 8 of 9 | 2 | ENSP00000465737.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251462Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461652Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727144
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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not specified Uncertain:1
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Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.N216S variant (also known as c.647A>G), located in coding exon 4 of the SMAD4 gene, results from an A to G substitution at nucleotide position 647. The asparagine at codon 216 is replaced by serine, an amino acid with highly similar properties. In a study of 98 patients from high-risk colorectal cancer families, without mutations in the mismatch repair genes, this variant was seen in one patient, who met the Bethesda criteria (Martin-Morales L et al. PLoS ONE. 2018 Sep;13:e0203885). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual from a high-risk colorectal cancer family (PMID: 30256826); This variant is associated with the following publications: (PMID: 15235019, 18823382, 22992590, 30256826) -
Juvenile polyposis syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at