1-45334484-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001407075.1(MUTYH):c.-135G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,614,066 control chromosomes in the GnomAD database, including 3,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 244 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3499 hom. )

Consequence

MUTYH
NM_001407075.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:23O:1

Conservation

PhyloP100: -0.185

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018110275).

BP6

Variant 1-45334484-C-T is Benign according to our data. Variant chr1-45334484-C-T is described in ClinVar as [Benign]. Clinvar id is 41760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45334484-C-T is described in Lovd as [Benign]. Variant chr1-45334484-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.22G>A	p.Val8Met	missense_variant	Exon 2 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.22G>A	p.Val8Met	missense_variant	Exon 2 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.568G>A		non_coding_transcript_exon_variant	Exon 6 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

7118

AN:

152136

Hom.:

244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.0385

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0317

Gnomad FIN

AF:

0.0750

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0733

Gnomad OTH

AF:

0.0387

GnomAD3 exomes

AF:

0.0485

AC:

12191

AN:

251474

Hom.:

402

AF XY:

0.0496

AC XY:

6738

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.0174

Gnomad ASJ exome

AF:

0.0430

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0325

Gnomad FIN exome

AF:

0.0748

Gnomad NFE exome

AF:

0.0709

Gnomad OTH exome

AF:

0.0485

GnomAD4 exome

AF:

0.0653

AC:

95456

AN:

1461812

Hom.:

3499

Cov.:

AF XY:

0.0646

AC XY:

46945

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00986

Gnomad4 AMR exome

AF:

0.0193

Gnomad4 ASJ exome

AF:

0.0428

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0336

Gnomad4 FIN exome

AF:

0.0748

Gnomad4 NFE exome

AF:

0.0742

Gnomad4 OTH exome

AF:

0.0595

GnomAD4 genome

AF:

0.0467

AC:

7117

AN:

152254

Hom.:

244

Cov.:

AF XY:

0.0460

AC XY:

3425

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0108

Gnomad4 AMR

AF:

0.0305

Gnomad4 ASJ

AF:

0.0418

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0315

Gnomad4 FIN

AF:

0.0750

Gnomad4 NFE

AF:

0.0733

Gnomad4 OTH

AF:

0.0383

Alfa

AF:

0.0628

Hom.:

909

Bravo

AF:

0.0422

TwinsUK

AF:

0.0725

AC:

269

ALSPAC

AF:

0.0799

AC:

308

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0694

AC:

597

ExAC

AF:

0.0491

AC:

5967

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0652

EpiControl

AF:

0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 2

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Mar 27, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aug 04, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Carcinoma of colon

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Val22Met variant has been previously reported in the literature in 234 of 7042 (frequency of 0.033) probands with FAP, colorectal cancer, prostate cancer, endometrial cancer and lung cancer, and was also identified in 253 of 6558 (frequency of 0.039) controls increasing the likelihood that this is a low frequency benign variant (Agalliu_2010, Alhopuro_2005, Ali_2008, Al-Tassan_2002, Ashton_2009, Croitoru_2004, Gorgens_2006, Isidro_2004, Kambara_2004, Shimura_2001, Shin_2007). Functional assays of the p.Val22Met variant reveal it to be as active as the WT with full glycosylase activity. This variant is not expected to have clinical significance because it is reported in dbSNP as a common polymorphism (dbSNP#: rs3219484), but no frequency informationw as provided. This residue is not highly conserved in mammals and computational analyses (________, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant is classified as benign. -

Breast carcinoma

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.6

DANN

Benign

0.97

DEOGEN2

Benign

0.073

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

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.63

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

MetaRNN

Benign

0.0018

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.4

.;.;.;.;.;.;L;L;L;.;.;.;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.45

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.073

Sift

Uncertain

0.0070

D;D;D;D;T;D;D;D;D;D;D;T;D;D;T

Sift4G

Pathogenic

0.0

D;T;D;T;T;T;D;T;T;D;D;D;D;D;D

Polyphen

0.18, 0.28

.;.;.;.;.;.;B;B;.;.;B;.;.;.;.

Vest4

0.17

MPC

0.12

ClinPred

0.0056

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

gMVP

0.19

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

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