rs26279

Positions:

chr5-80873118-G-A

Variant summary

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

The NM_002439.5(MSH3):c.3133G>A(p.Ala1045Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,610,178 control chromosomes in the GnomAD database, including 415,407 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 37907 hom., cov: 32)

Exomes 𝑓: 0.72 ( 377500 hom. )

Consequence

MSH3
NM_002439.5 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.92

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=8.821013E-7).

BP6

Variant 5-80873118-G-A is Benign according to our data. Variant chr5-80873118-G-A is described in ClinVar as [Benign]. Clinvar id is 822964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80873118-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 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.3133G>A	p.Ala1045Thr	missense_variant, splice_region_variant	23/24	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7 linkuse as main transcript	c.3133G>A	p.Ala1045Thr	missense_variant, splice_region_variant	23/24	1	NM_002439.5	ENSP00000265081	P2

Frequencies

GnomAD3 genomes

AF:

0.706

AC:

107286

AN:

151968

Hom.:

37881

Cov.:

show subpopulations

Gnomad AFR

AF:

0.668

Gnomad AMI

AF:

0.793

Gnomad AMR

AF:

0.703

Gnomad ASJ

AF:

0.688

Gnomad EAS

AF:

0.754

Gnomad SAS

AF:

0.796

Gnomad FIN

AF:

0.729

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.716

Gnomad OTH

AF:

0.700

GnomAD3 exomes

AF:

0.729

AC:

183208

AN:

251172

Hom.:

67007

AF XY:

0.730

AC XY:

99085

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.664

Gnomad AMR exome

AF:

0.756

Gnomad ASJ exome

AF:

0.706

Gnomad EAS exome

AF:

0.747

Gnomad SAS exome

AF:

0.793

Gnomad FIN exome

AF:

0.734

Gnomad NFE exome

AF:

0.714

Gnomad OTH exome

AF:

0.698

GnomAD4 exome

AF:

0.719

AC:

1047769

AN:

1458094

Hom.:

377500

Cov.:

AF XY:

0.720

AC XY:

522185

AN XY:

725564

show subpopulations

Gnomad4 AFR exome

AF:

0.655

Gnomad4 AMR exome

AF:

0.748

Gnomad4 ASJ exome

AF:

0.703

Gnomad4 EAS exome

AF:

0.753

Gnomad4 SAS exome

AF:

0.795

Gnomad4 FIN exome

AF:

0.729

Gnomad4 NFE exome

AF:

0.713

Gnomad4 OTH exome

AF:

0.712

GnomAD4 genome

AF:

0.706

AC:

107363

AN:

152084

Hom.:

37907

Cov.:

AF XY:

0.707

AC XY:

52586

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.668

Gnomad4 AMR

AF:

0.703

Gnomad4 ASJ

AF:

0.688

Gnomad4 EAS

AF:

0.754

Gnomad4 SAS

AF:

0.798

Gnomad4 FIN

AF:

0.729

Gnomad4 NFE

AF:

0.716

Gnomad4 OTH

AF:

0.698

Alfa

AF:

0.707

Hom.:

98298

Bravo

AF:

0.700

TwinsUK

AF:

0.719

AC:

2667

ALSPAC

AF:

0.716

AC:

2759

ESP6500AA

AF:

0.666

AC:

2934

ESP6500EA

AF:

0.709

AC:

6101

ExAC

AF:

0.730

AC:

88681

Asia WGS

AF:

0.737

AC:

2563

AN:

3476

EpiCase

AF:

0.692

EpiControl

AF:

0.696

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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: 25966119, 17205513, 20708344) -

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

0.066

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

4.7

DANN

Benign

0.73

DEOGEN2

Benign

0.16

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.17

MetaRNN

Benign

8.8e-7

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.24

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.10

REVEL

Benign

0.11

Sift

Benign

0.55

Sift4G

Benign

0.53

Polyphen

0.075

Vest4

0.018

MPC

0.026

ClinPred

0.0025

GERP RS

-2.5

Varity_R

0.025

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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