rs1553122813

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001048174.2(MUTYH):​c.1540C>T​(p.His514Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

MUTYH
NM_001048174.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.484
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06399438).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MUTYHNM_001128425.2 linkuse as main transcriptc.1624C>T p.His542Tyr missense_variant 16/16 ENST00000710952.2 NP_001121897.1
MUTYHNM_001048174.2 linkuse as main transcriptc.1540C>T p.His514Tyr missense_variant 16/16 ENST00000456914.7 NP_001041639.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MUTYHENST00000710952.2 linkuse as main transcriptc.1624C>T p.His542Tyr missense_variant 16/16 NM_001128425.2 ENSP00000518552
MUTYHENST00000456914.7 linkuse as main transcriptc.1540C>T p.His514Tyr missense_variant 16/161 NM_001048174.2 ENSP00000407590 A1Q9UIF7-6

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 05, 2022This missense variant replaces histidine with tyrosine at codon 542 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
12
DANN
Benign
0.83
DEOGEN2
Benign
0.047
.;.;.;.;.;.;T;.;.;.;.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.051
N
LIST_S2
Benign
0.81
.;.;T;.;T;T;T;T;T;T;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.064
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
.;.;.;.;.;.;N;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.35
N;N;N;N;N;N;N;N;N;N;N;.
REVEL
Benign
0.034
Sift
Benign
0.11
T;T;T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.23
T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.031, 0.19
.;.;.;.;.;.;B;B;.;.;B;.
Vest4
0.15
MutPred
0.25
.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at H542 (P = 0.0097);.;
MVP
0.56
MPC
0.14
ClinPred
0.29
T
GERP RS
1.1
Varity_R
0.12
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1553122813; hg19: chr1-45795004; API