5-80854162-A-G

Position:

chr5-80854162-A-G

Variant summary

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

The NM_002439.5(MSH3):c.2846A>G(p.Gln949Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,612,888 control chromosomes in the GnomAD database, including 590,189 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 Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 57289 hom., cov: 30)

Exomes 𝑓: 0.85 ( 532900 hom. )

Consequence

MSH3
NM_002439.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.429

Variant links:

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

MSH3 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=4.7514077E-6).

BP6

Variant 5-80854162-A-G is Benign according to our data. Variant chr5-80854162-A-G is described in ClinVar as [Benign]. Clinvar id is 821892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80854162-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH3	NM_002439.5 linkuse as main transcript	c.2846A>G	p.Gln949Arg	missense_variant	21/24	ENST00000265081.7	NP_002430.3	P20585

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MSH3	ENST00000265081.7 linkuse as main transcript	c.2846A>G	p.Gln949Arg	missense_variant	21/24	1	NM_002439.5	ENSP00000265081.6	P20585
MSH3	ENST00000658259.1 linkuse as main transcript	c.2678A>G	p.Gln893Arg	missense_variant	21/24			ENSP00000499617.1	A0A590UJW0
MSH3	ENST00000667069.1 linkuse as main transcript	c.2651A>G	p.Gln884Arg	missense_variant	19/22			ENSP00000499502.1	A0A590UJN8
MSH3	ENST00000670357.1 linkuse as main transcript	n.*170A>G		non_coding_transcript_exon_variant	22/25			ENSP00000499791.1	A0A590UKC9
MSH3	ENST00000670357.1 linkuse as main transcript	n.*170A>G		3_prime_UTR_variant	22/25			ENSP00000499791.1	A0A590UKC9

Frequencies

GnomAD3 genomes

AF:

0.867

AC:

131774

AN:

151978

Hom.:

57227

Cov.:

show subpopulations

Gnomad AFR

AF:

0.892

Gnomad AMI

AF:

0.878

Gnomad AMR

AF:

0.867

Gnomad ASJ

AF:

0.802

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.885

Gnomad FIN

AF:

0.877

Gnomad MID

AF:

0.794

Gnomad NFE

AF:

0.843

Gnomad OTH

AF:

0.860

GnomAD3 exomes

AF:

0.873

AC:

219003

AN:

250730

Hom.:

95934

AF XY:

0.869

AC XY:

117718

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.893

Gnomad AMR exome

AF:

0.913

Gnomad ASJ exome

AF:

0.830

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.882

Gnomad FIN exome

AF:

0.879

Gnomad NFE exome

AF:

0.840

Gnomad OTH exome

AF:

0.843

GnomAD4 exome

AF:

0.853

AC:

1246501

AN:

1460792

Hom.:

532900

Cov.:

AF XY:

0.853

AC XY:

619625

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.888

Gnomad4 AMR exome

AF:

0.907

Gnomad4 ASJ exome

AF:

0.824

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.883

Gnomad4 FIN exome

AF:

0.875

Gnomad4 NFE exome

AF:

0.843

Gnomad4 OTH exome

AF:

0.852

GnomAD4 genome

AF:

0.867

AC:

131897

AN:

152096

Hom.:

57289

Cov.:

AF XY:

0.869

AC XY:

64654

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.892

Gnomad4 AMR

AF:

0.867

Gnomad4 ASJ

AF:

0.802

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.886

Gnomad4 FIN

AF:

0.877

Gnomad4 NFE

AF:

0.843

Gnomad4 OTH

AF:

0.861

Alfa

AF:

0.844

Hom.:

133627

Bravo

AF:

0.868

TwinsUK

AF:

0.848

AC:

3144

ALSPAC

AF:

0.833

AC:

3211

ESP6500AA

AF:

0.894

AC:

3938

ESP6500EA

AF:

0.835

AC:

7185

ExAC

AF:

0.873

AC:

105961

Asia WGS

AF:

0.932

AC:

3242

AN:

3478

EpiCase

AF:

0.825

EpiControl

AF:

0.831

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 17205513) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.3

DANN

Benign

0.86

DEOGEN2

Benign

0.16

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0000048

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.32

PrimateAI

Benign

0.20

PROVEAN

Benign

0.58

REVEL

Benign

0.28

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.033

MPC

0.027

ClinPred

0.0013

GERP RS

0.29

Varity_R

0.080

gMVP

0.77

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