1-45332446-G-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_001048174.2(MUTYH):c.649C>A(p.Arg217Ser) variant causes a missense change involving the alteration of a 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 Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217L) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
MUTYH
NM_001048174.2 missense
NM_001048174.2 missense
Scores
14
4
1
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 7.25
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 11 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001048174.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-45332446-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 1-45332446-G-T is Pathogenic according to our data. Variant chr1-45332446-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MUTYH | ENST00000456914.7 | c.649C>A | p.Arg217Ser | missense_variant | Exon 9 of 16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
| ENSG00000288208 | ENST00000671898.1 | n.1237C>A | non_coding_transcript_exon_variant | Exon 13 of 21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.;T;.;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;H;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0, 1.0
.;.;.;.;.;D;D;.;D;.;.;.
Vest4
MutPred
0.93
.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0289);.;.;.;
MVP
MPC
0.57
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.