rs144111588

chr1-45330550-C-Gchr1-45330550-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001048174.2(MUTYH):c.1400G>C(p.Arg467Pro) 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 pathogenic outcome for this variant. 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. R467H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.1484G>C	p.Arg495Pro	missense_variant	15/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.1400G>C	p.Arg467Pro	missense_variant	15/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.1484G>C	p.Arg495Pro	missense_variant	15/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.1400G>C	p.Arg467Pro	missense_variant	15/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

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

Aug 08, 2019

This sequence change replaces arginine with proline at codon 495 of the MUTYH protein (p.Arg495Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	23
Dann	Benign	0.96
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D;N;N;N;N;N;N;N;N;D;N;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.090	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0050, 0.0080, 0.0	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.76
MutPred		0.59		.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 3e-04);.;
MVP		0.93
MPC		0.17
ClinPred		0.41	T
GERP RS		2.6
Varity_R		0.84
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144111588; hg19: chr1-45796222;