6-31740551-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

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

Publications

58 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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

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
MSH5-SAPCD1	ENST00000493662.6 link	n.85C>T		non_coding_transcript_exon_variant	Exon 2 of 29	1		ENSP00000417871.2

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

GnomAD2 exomes

AF:

0.126

AC:

15944

AN:

126162

AF XY:

0.123

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 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

African (AFR)

AF:

0.0306

AC:

893

AN:

29224

American (AMR)

AF:

0.197

AC:

5879

AN:

29810

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

1021

AN:

23930

East Asian (EAS)

AF:

0.213

AC:

7238

AN:

33982

South Asian (SAS)

AF:

0.129

AC:

9961

AN:

77072

European-Finnish (FIN)

AF:

0.177

AC:

8622

AN:

48762

Middle Eastern (MID)

AF:

0.0502

AC:

243

AN:

4836

European-Non Finnish (NFE)

AF:

0.0900

AC:

96329

AN:

1069930

Other (OTH)

AF:

0.0974

AC:

5520

AN:

56664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

6903

13806

20709

27612

34515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3620

7240

10860

14480

18100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0930

AC:

14142

AN:

152128

Hom.:

832

Cov.:

AF XY:

0.0996

AC XY:

7406

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0350

AC:

1452

AN:

41536

American (AMR)

AF:

0.165

AC:

2516

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0404

AC:

140

AN:

3464

East Asian (EAS)

AF:

0.149

AC:

770

AN:

5156

South Asian (SAS)

AF:

0.132

AC:

634

AN:

4814

European-Finnish (FIN)

AF:

0.177

AC:

1869

AN:

10584

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0960

AC:

6524

AN:

67970

Other (OTH)

AF:

0.0772

AC:

163

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

630

1259

1889

2518

3148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0949

Hom.:

1053

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

(source)

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

PhyloP100

0.039

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over