rs192816572

Positions:

• chr1-45331241-C-A
• chr1-45331241-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001048174.2(MUTYH):​c.1333G>T​(p.Ala445Ser) 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. A445T) 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: 0.854

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45331240-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1417G>T	p.Ala473Ser	missense_variant	14/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.1333G>T	p.Ala445Ser	missense_variant	14/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1417G>T	p.Ala473Ser	missense_variant	14/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.1333G>T	p.Ala445Ser	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

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

The p.A473S variant (also known as c.1417G>T), located in coding exon 14 of the MUTYH gene, results from a G to T substitution at nucleotide position 1417. The alanine at codon 473 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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	0.091
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.16	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	.;.;T;.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.21	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.52
Sift	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.030, 0.018	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.27
MutPred		0.75		.;.;.;.;.;.;.;.;.;.;Gain of glycosylation at A473 (P = 0.0298);.;
MVP		0.88
MPC		0.11
ClinPred		0.18	T
GERP RS		4.3
Varity_R		0.043
gMVP		0.28

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: chr1-45796913;