rs1553129798

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001048174.2(MUTYH):​c.301G>C​(p.Ala101Pro) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MUTYH
NM_001048174.2 missense

Scores

4
13
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_001048174.2
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MUTYHNM_001048174.2 linkc.301G>C p.Ala101Pro missense_variant 4/16 ENST00000456914.7 NP_001041639.1 Q9UIF7-6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MUTYHENST00000456914.7 linkc.301G>C p.Ala101Pro missense_variant 4/161 NM_001048174.2 ENSP00000407590.2 Q9UIF7-6
ENSG00000288208ENST00000671898.1 linkn.889G>C non_coding_transcript_exon_variant 8/21 ENSP00000499896.1 A0A5F9ZGZ0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 25, 2020This sequence change replaces alanine with proline at codon 129 of the MUTYH protein (p.Ala129Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
.;.;.;.;.;T;.;.;.;T;T
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
.;D;.;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.72
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.68
D
MutationAssessor
Uncertain
2.3
.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.5
D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.012
D;D;D;D;D;D;D;D;D;T;T
Sift4G
Uncertain
0.023
D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.99, 1.0
.;.;.;.;.;D;D;.;D;.;.
Vest4
0.82
MutPred
0.55
.;.;.;.;.;.;.;.;Gain of sheet (P = 0.0221);.;.;
MVP
0.98
MPC
0.62
ClinPred
0.98
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553129798; hg19: chr1-45798960; API