1-45331833-C-G

Position:

chr1-45331833-C-G

Variant summary

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

The NM_001048174.2(MUTYH):c.930G>C(p.Gln310His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,603,502 control chromosomes in the GnomAD database, including 56,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q310R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.27 ( 5852 hom., cov: 33)

Exomes 𝑓: 0.26 ( 50945 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21O:1

Conservation

PhyloP100: -0.265

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=0.0010225773).

BP6

Variant 1-45331833-C-G is Benign according to our data. Variant chr1-45331833-C-G is described in ClinVar as [Benign]. Clinvar id is 41767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331833-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.930G>C	p.Gln310His	missense_variant	12/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.930G>C	p.Gln310His	missense_variant	12/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 linkuse as main transcript	n.1518G>C		non_coding_transcript_exon_variant	16/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40958

AN:

152016

Hom.:

5824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.264

Gnomad AMI

AF:

0.274

Gnomad AMR

AF:

0.400

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.412

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.215

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.297

GnomAD3 exomes

AF:

0.290

AC:

67377

AN:

232316

Hom.:

10651

AF XY:

0.277

AC XY:

34951

AN XY:

126078

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.263

Gnomad EAS exome

AF:

0.397

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.244

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

AF:

0.260

AC:

377531

AN:

1451368

Hom.:

50945

Cov.:

AF XY:

0.257

AC XY:

185520

AN XY:

721162

show subpopulations

Gnomad4 AFR exome

AF:

0.266

Gnomad4 AMR exome

AF:

0.477

Gnomad4 ASJ exome

AF:

0.261

Gnomad4 EAS exome

AF:

0.420

Gnomad4 SAS exome

AF:

0.233

Gnomad4 FIN exome

AF:

0.228

Gnomad4 NFE exome

AF:

0.249

Gnomad4 OTH exome

AF:

0.270

GnomAD4 genome

AF:

0.270

AC:

41017

AN:

152134

Hom.:

5852

Cov.:

AF XY:

0.270

AC XY:

20054

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.401

Gnomad4 ASJ

AF:

0.262

Gnomad4 EAS

AF:

0.412

Gnomad4 SAS

AF:

0.238

Gnomad4 FIN

AF:

0.215

Gnomad4 NFE

AF:

0.243

Gnomad4 OTH

AF:

0.305

Alfa

AF:

0.250

Hom.:

1622

Bravo

AF:

0.287

TwinsUK

AF:

0.249

AC:

922

ALSPAC

AF:

0.255

AC:

981

ESP6500AA

AF:

0.264

AC:

1161

ESP6500EA

AF:

0.249

AC:

2143

ExAC

AF:

0.268

AC:

32463

Asia WGS

AF:

0.359

AC:

1247

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 12, 2017	p.Ser372Phe in exon 12 of MUTYH: This variant is not expected to have clinical s ignificance because it has been identified in 49% (15851/32596) of Latino chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs3219489). -

not provided

Benign:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23108399, 22703879, 22780951, 22926731, 18422726, 20149637, 22466227, 18823566, 19161591, 23499241, 23460202, 24728327, 18534194, 26377631, 25820570, 27153395, 29954149, 28628107, 27705013, 31027119, 30564557, 23618615, 31104418) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Familial adenomatous polyposis 2

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 28, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2015	- -

Familial multiple polyposis syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Gln338His variant was not identified in the literature. The p.Gln338 residue is not conserved in mammals and this variant is listed in dbSNP as a common polymorphism in different populations of origin with an average heterozygosity reported as 0.403+/-0.198 (dbSNP#: rs3219489), increasing the likelihood that the variant has no clinical significance. In summary, based on the above information, this variant is classified as benign. -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.086

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

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.44

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

MetaRNN

Benign

0.0010

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

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.0

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

REVEL

Benign

0.043

Sift

Benign

0.17

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

Sift4G

Benign

0.12

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

Polyphen

0.65, 0.33, 0.34

.;.;.;.;.;P;B;.;B;.;.

Vest4

0.13

MutPred

0.12

.;.;.;.;.;.;.;.;Loss of sheet (P = 0.0457);.;.;

MPC

0.13

ClinPred

0.016

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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