rs1553129230

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_001048174.2(MUTYH):c.418G>A(p.Glu140Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. E140D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MUTYH
NM_001048174.2 missense, splice_region

Scores

Splicing: ADA: 0.002830

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.51

Variant links:

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]

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a helix (size 13) in uniprot entity MUTYH_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr1-45332918-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3400141.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.418G>A	p.Glu140Lys	missense_variant, splice_region_variant	Exon 6 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.418G>A	p.Glu140Lys	missense_variant, splice_region_variant	Exon 6 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1006G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:2

Feb 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 490037). 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 168 of the MUTYH protein (p.Glu168Lys). -

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Jun 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E168K variant (also known as c.502G>A), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 502. The glutamic acid at codon 168 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;.;.;.;.;T;.;.;.;T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;.;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.9

.;.;.;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;.;.;.;.;D;D;.;D;.;.

Vest4

0.81

MutPred

0.47

.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0116);.;.;

MVP

0.95

MPC

0.55

ClinPred

0.97

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.95

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0028

dbscSNV1_RF

Benign

0.21

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over