NM_001048174.2:c.398A>G

Variant names:

• chr1-45332940-T-C
• NM_001048174.2:c.398A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001048174.2(MUTYH):​c.398A>G​(p.Asp133Gly) variant causes a missense change. 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. D133H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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 chr1-45332941-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.398A>G	p.Asp133Gly	missense_variant	Exon 6 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.398A>G	p.Asp133Gly	missense_variant	Exon 6 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.986A>G		non_coding_transcript_exon_variant	Exon 10 of 21			ENSP00000499896.1

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D161G variant (also known as c.482A>G), located in coding exon 6 of the MUTYH gene, results from an A to G substitution at nucleotide position 482. The aspartic acid at codon 161 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;.;.;.;T;.;.;.;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.070	T;D;T;T;T;D;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.96, 0.95, 0.96	.;.;.;.;.;D;P;.;D;.;.
Vest4		0.41
MutPred		0.53		.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0545);.;.;
MVP		0.98
MPC		0.37
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.60

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: chr1-45798612;