rs1553126848
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_001048174.2(MUTYH):c.940_962del(p.Cys314GlyfsTer182) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
MUTYH
NM_001048174.2 frameshift
NM_001048174.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.53
Genes affected
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 1-45331800-CCAGGGCTCCGAGGGAGGCAGGCA-C is Pathogenic according to our data. Variant chr1-45331800-CCAGGGCTCCGAGGGAGGCAGGCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 533319.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001048174.2 | c.940_962del | p.Cys314GlyfsTer182 | frameshift_variant | 12/16 | ENST00000456914.7 | |
MUTYH | NM_001128425.2 | c.1024_1046del | p.Cys342GlyfsTer182 | frameshift_variant | 12/16 | ENST00000710952.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.940_962del | p.Cys314GlyfsTer182 | frameshift_variant | 12/16 | 1 | NM_001048174.2 | A1 | |
MUTYH | ENST00000710952.2 | c.1024_1046del | p.Cys342GlyfsTer182 | frameshift_variant | 12/16 | NM_001128425.2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 04, 2021 | For these reasons, this variant has been classified as Pathogenic. Several different frameshift variants downstream of this variant (p.Pro367Glnfs*164, p.Pro405Leufs*123, and p.Ser518Alafs*54) have been determined to be likely pathogenic or pathogenic (Invitae). These truncations disrupts the conserved PCNA binding motif of MUTYH (Gln526-Phe533, also known as Gln512-Phe519 in the literature because of transcript nomenclature differences), which has been shown to be critical for MUTYH-PCNA binding (PMID: 11092888, 26377631). This suggests that disruption of this region of the MUTYH protein is causative of disease. This variant has not been reported in the literature in individuals with MUTYH-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MUTYH gene (p.Cys342Glyfs*182). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 208 amino acids of the MUTYH protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at