18-51047193-GA-GAA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005359.6(SMAD4):c.153dupA(p.Asp52ArgfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005359.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.153dupA | p.Asp52ArgfsTer2 | frameshift_variant | Exon 2 of 12 | ENST00000342988.8 | NP_005350.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.153dupA | p.Asp52ArgfsTer2 | frameshift_variant | Exon 2 of 12 | 5 | NM_005359.6 | ENSP00000341551.3 | ||
ENSG00000267699 | ENST00000590722.2 | n.*176dupA | non_coding_transcript_exon_variant | Exon 3 of 9 | 2 | ENSP00000465737.1 | ||||
ENSG00000267699 | ENST00000590722.2 | n.*176dupA | 3_prime_UTR_variant | Exon 3 of 9 | 2 | ENSP00000465737.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The c.153dupA pathogenic mutation, located in coding exon 1 of the SMAD4 gene, results from a duplication of A at nucleotide position 153, causing a translational frameshift with a predicted alternate stop codon. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
not provided Pathogenic:1
This duplication of one nucleotide in SMAD4 is denoted c.153dupA at the cDNA level and p.Asp52ArgfsX2 (D52RfsX2) at the protein level. The normal sequence, with the base that is duplicated in braces, is GAAAAA[A]GATG. The duplication causes a frameshift which changes an Aspartic Acid to an Arginine at codon 52, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. -
Juvenile polyposis syndrome Pathogenic:1
This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 187217). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp52Argfs*2) in the SMAD4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at