rs377767376
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_005359.6(SMAD4):c.1587dupA(p.His530ThrfsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_005359.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.1587dupA | p.His530ThrfsTer47 | frameshift_variant | Exon 12 of 12 | ENST00000342988.8 | NP_005350.1 | |
SMAD4 | NM_001407041.1 | c.1587dupA | p.His530ThrfsTer47 | frameshift_variant | Exon 12 of 12 | NP_001393970.1 | ||
SMAD4 | NM_001407042.1 | c.1587dupA | p.His530ThrfsTer47 | frameshift_variant | Exon 12 of 12 | NP_001393971.1 | ||
SMAD4 | NR_176265.1 | n.2238dupA | non_coding_transcript_exon_variant | Exon 13 of 13 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Juvenile polyposis syndrome Pathogenic:1
This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the SMAD4 gene (p.His530Thrfs*47). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acids of the SMAD4 protein and extend the protein by an additional 24 amino acids. For these reasons, this variant has been classified as Pathogenic. This variant has been reported in an individual affected with juvenile polyposis syndrome (PMID: 18178612, 26572829). It has also been observed to be de novo in an individual affected with juvenile polyposis and hereditary hemorrhagic telangiectasia syndrome (Invitae). This variant is also known as c.1586_1587dupA (p.L529LfsX9) in the literature. ClinVar contains an entry for this variant (Variation ID: 24867). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at