dbSNP rs75321043: MUTYH:p.Gly25Val (chr1-45334474-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001128425.2(MUTYH):c.74G>T(p.Gly25Val) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G25D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MUTYH
NM_001128425.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Publications

0 publications found

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]

MUTYH Gene-Disease associations (from GenCC):

familial adenomatous polyposis 2
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
colorectal cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.093682796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2 link	c.74G>T	p.Gly25Val	missense_variant	Exon 2 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 link	c.32G>T	p.Gly11Val	missense_variant	Exon 2 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUTYH	ENST00000710952.2 link	c.74G>T	p.Gly25Val	missense_variant	Exon 2 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7 link	c.32G>T	p.Gly11Val	missense_variant	Exon 2 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1 link	n.578G>T		non_coding_transcript_exon_variant	Exon 6 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;.;.;.;.;.;T;.;.;.;.;.;T;T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.90

.;.;D;.;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.094

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.3

.;.;.;.;.;.;L;L;L;.;.;.;.;.;.

PhyloP100

1.3

PrimateAI

Benign

0.22

PROVEAN

Benign

0.15

N;N;N;N;N;N;N;N;N;N;N;D;N;N;N

REVEL

Benign

0.051

Sift

Benign

0.047

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;T;D;D;D;T;D;D;D;T;T;T;T;T

Polyphen

0.88, 0.93, 0.34

.;.;.;.;.;.;P;P;.;.;B;.;.;.;.

Vest4

0.25

MutPred

0.25

.;.;.;.;.;.;Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);.;Loss of relative solvent accessibility (P = 0.0071);.;.;.;.;

MVP

0.81

MPC

0.21

ClinPred

0.28

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over