1-45331476-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.1183G>A(p.Glu395Lys) 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. E395?) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730

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 chr1-45331474-TTC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552265.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1267G>A	p.Glu423Lys	missense_variant	13/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.1183G>A	p.Glu395Lys	missense_variant	13/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1267G>A	p.Glu423Lys	missense_variant	13/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.1183G>A	p.Glu395Lys	missense_variant	13/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 423 of the MUTYH protein (p.Glu423Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.0041
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.75	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	0.73	D;D;D;D;D;D;D;N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.41
Sift	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.15, 0.81, 0.72	.;.;.;.;.;.;B;P;.;.;P;.
Vest4		0.28
MutPred		0.73		.;.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0021);.;
MVP		0.93
MPC		0.13
ClinPred		0.52	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.72

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: chr1-45797148;