rs140118273

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001048174.2(MUTYH):c.1460C>T(p.Ser487Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,140 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0098 ( 12 hom., cov: 31)

Exomes 𝑓: 0.011 ( 140 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27O:1

Conservation

PhyloP100: 1.76

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=0.004083574).

BP6

Variant 1-45329412-G-A is Benign according to our data. Variant chr1-45329412-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45329412-G-A is described in Lovd as [Benign]. Variant chr1-45329412-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00975 (1485/152264) while in subpopulation NFE AF= 0.0118 (800/68018). AF 95% confidence interval is 0.0111. There are 12 homozygotes in gnomad4. There are 693 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.1460C>T	p.Ser487Phe	missense_variant	Exon 16 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MUTYH	ENST00000456914.7 link	c.1460C>T	p.Ser487Phe	missense_variant	Exon 16 of 16	1	NM_001048174.2	ENSP00000407590.2	Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.*203C>T		non_coding_transcript_exon_variant	Exon 21 of 21			ENSP00000499896.1	A0A5F9ZGZ0
ENSG00000288208	ENST00000671898.1 link	n.*203C>T		3_prime_UTR_variant	Exon 21 of 21			ENSP00000499896.1	A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.00977

AC:

1487

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00816

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.00841

AC:

2115

AN:

251444

Hom.:

AF XY:

0.00834

AC XY:

1134

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00738

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.0234

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00278

Gnomad FIN exome

AF:

0.00476

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0112

AC:

16371

AN:

1461876

Hom.:

140

Cov.:

AF XY:

0.0108

AC XY:

7837

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00944

Gnomad4 AMR exome

AF:

0.00700

Gnomad4 ASJ exome

AF:

0.0232

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00253

Gnomad4 FIN exome

AF:

0.00515

Gnomad4 NFE exome

AF:

0.0123

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.00975

AC:

1485

AN:

152264

Hom.:

Cov.:

AF XY:

0.00931

AC XY:

693

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00816

Gnomad4 AMR

AF:

0.00987

Gnomad4 ASJ

AF:

0.0288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0126

AC:

108

ExAC

AF:

0.00787

AC:

956

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:11Other:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Sep 10, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Jul 16, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 18, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:6

Feb 20, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2015

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 20, 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. -

not provided

Benign:5

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH: BP4, BS1, BS2 -

Familial adenomatous polyposis 2

Benign:4

Apr 14, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Familial multiple polyposis syndrome

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is not expected to have clinical significance because it does not occur at a conserved amino acid residue, is not located near a splice junction, is listed in dbSNP (rs140118273), and is reported as benign in multiple publications. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.080

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.068

LIST_S2

Uncertain

0.88

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

MetaRNN

Benign

0.0041

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

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

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Benign

0.23

Sift

Uncertain

0.014

D;T;D;T;D;T;D;D;D;D;D;.

Sift4G

Uncertain

0.034

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

Polyphen

0.14, 0.0040, 0.0030

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

Vest4

0.20

MVP

0.59

MPC

0.18

ClinPred

0.0071

GERP RS

0.17

Varity_R

0.041

gMVP

0.22

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