rs2075789

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_172166.4(MSH5):c.85C>T(p.Pro29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,526,338 control chromosomes in the GnomAD database, including 8,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.093 ( 832 hom., cov: 31)

Exomes 𝑓: 0.099 ( 7777 hom. )

Consequence

MSH5
NM_172166.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.0390

Variant links:

Genes affected

MSH5 (HGNC:7328): (mutS homolog 5) This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

MSH5 links:

MSH5-SAPCD1 (HGNC:41994): (MSH5-SAPCD1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring mutS homolog 5 (MSH5) and chromosome 6 open reading frame 26 (C6orf26) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

MSH5-SAPCD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004588902).

BP6

Variant 6-31740551-C-T is Benign according to our data. Variant chr6-31740551-C-T is described in ClinVar as [Benign]. Clinvar id is 403111.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4 link	c.85C>T	p.Pro29Ser	missense_variant	Exon 2 of 25	ENST00000375750.9	NP_751898.1	O43196-1A0A024RCM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9 link	c.85C>T	p.Pro29Ser	missense_variant	Exon 2 of 25	1	NM_172166.4	ENSP00000364903.3		O43196-1
MSH5-SAPCD1	ENST00000493662.6 link	n.85C>T		non_coding_transcript_exon_variant	Exon 2 of 29	1		ENSP00000417871.2		A0A024RCV8

Frequencies

GnomAD3 genomes

AF:

0.0930

AC:

14131

AN:

152010

Hom.:

830

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0350

Gnomad AMI

AF:

0.0626

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.0404

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.177

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0960

Gnomad OTH

AF:

0.0775

GnomAD3 exomes

AF:

0.126

AC:

15944

AN:

126162

Hom.:

1217

AF XY:

0.123

AC XY:

8464

AN XY:

68762

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.0424

Gnomad EAS exome

AF:

0.138

Gnomad SAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.0954

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0988

AC:

135706

AN:

1374210

Hom.:

7777

Cov.:

AF XY:

0.0991

AC XY:

67201

AN XY:

678122

show subpopulations

Gnomad4 AFR exome

AF:

0.0306

Gnomad4 AMR exome

AF:

0.197

Gnomad4 ASJ exome

AF:

0.0427

Gnomad4 EAS exome

AF:

0.213

Gnomad4 SAS exome

AF:

0.129

Gnomad4 FIN exome

AF:

0.177

Gnomad4 NFE exome

AF:

0.0900

Gnomad4 OTH exome

AF:

0.0974

GnomAD4 genome

AF:

0.0930

AC:

14142

AN:

152128

Hom.:

832

Cov.:

AF XY:

0.0996

AC XY:

7406

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0350

Gnomad4 AMR

AF:

0.165

Gnomad4 ASJ

AF:

0.0404

Gnomad4 EAS

AF:

0.149

Gnomad4 SAS

AF:

0.132

Gnomad4 FIN

AF:

0.177

Gnomad4 NFE

AF:

0.0960

Gnomad4 OTH

AF:

0.0772

Alfa

AF:

0.0916

Hom.:

682

Bravo

AF:

0.0890

TwinsUK

AF:

0.0912

AC:

338

ALSPAC

AF:

0.0823

AC:

317

ESP6500AA

AF:

0.0322

AC:

129

ESP6500EA

AF:

0.0830

AC:

669

ExAC

AF:

0.0822

AC:

8196

Asia WGS

AF:

0.176

AC:

611

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

MSH5-related disorder

Benign:1

Jul 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.7

DANN

Benign

0.92

DEOGEN2

Benign

0.074

T;T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.034

MetaRNN

Benign

0.0046

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;.;L;L

PROVEAN

Benign

-0.030

N;N;N;N;N

REVEL

Benign

0.057

Sift

Uncertain

0.022

D;D;D;D;D

Sift4G

Benign

0.11

T;T;D;D;D

Polyphen

0.0

B;B;.;B;B

Vest4

0.034

MPC

0.45

ClinPred

0.0040

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.51

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