chr5-112775683-C-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.477C>A(p.Tyr159Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y159Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000038.6 stop_gained
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.477C>A | p.Tyr159Ter | stop_gained | 5/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.477C>A | p.Tyr159Ter | stop_gained | 5/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 26, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change creates a premature translational stop signal (p.Tyr159*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 21779980, 27623068). ClinVar contains an entry for this variant (Variation ID: 928697). For these reasons, this variant has been classified as Pathogenic. - |
Familial multiple polyposis syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 12, 2019 | Variant summary: APC c.477C>A (p.Tyr159X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 247504 control chromosomes (gnomAD). c.477C>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Uchino_2016, Jarry_2011). A different nucleotide change (c.477C>G) resulting in the same codon effect (p.Tyr159X) has been cited as pathogenic in ClinVar (Variation ID: 246084) by two submitters (evaluation after 2014) and has been reported in multiple affected individuals (PMID: 19701947, 15951963, 20223039). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at