rs758262369

chr1-45331244-C-Achr1-45331244-C-Gchr1-45331244-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001048174.2(MUTYH):c.1330G>T(p.Gly444Cys) 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. G444R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1414G>T	p.Gly472Cys	missense_variant	14/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.1330G>T	p.Gly444Cys	missense_variant	14/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1414G>T	p.Gly472Cys	missense_variant	14/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.1330G>T	p.Gly444Cys	missense_variant	14/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.086
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.42	N
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;N;N;N;N;N;N;N;N;D;N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.030	D;T;T;T;T;T;T;T;T;D;D;T
Polyphen		0.97, 0.99, 0.99	.;.;.;.;.;.;D;D;.;.;D;.
Vest4		0.47
MutPred		0.59		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at P471 (P = 0.0285);.;
MVP		0.91
MPC		0.45
ClinPred		0.87	D
GERP RS		5.2
Varity_R		0.40
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45796916;