chr6-31762148-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_172166.4(MSH5):c.2356C>T(p.Pro786Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,030 control chromosomes in the GnomAD database, including 1,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.049 ( 341 hom., cov: 32)

Exomes 𝑓: 0.021 ( 757 hom. )

Consequence

MSH5
NM_172166.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.02

Publications

23 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015169978).

BP6

Variant 6-31762148-C-T is Benign according to our data. Variant chr6-31762148-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056743.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4 link	c.2356C>T	p.Pro786Ser	missense_variant	Exon 24 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.2356C>T	p.Pro786Ser	missense_variant	Exon 24 of 25	1	NM_172166.4	ENSP00000364903.3		O43196-1
MSH5-SAPCD1	ENST00000493662.6 link	n.2407C>T		non_coding_transcript_exon_variant	Exon 24 of 29	1		ENSP00000417871.2		A0A024RCV8

Frequencies

GnomAD3 genomes

AF:

0.0491

AC:

7470

AN:

152104

Hom.:

341

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0546

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.0703

GnomAD2 exomes

AF:

0.0298

AC:

7502

AN:

251442

AF XY:

0.0256

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0532

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.000489

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0381

GnomAD4 exome

AF:

0.0206

AC:

30176

AN:

1461808

Hom.:

757

Cov.:

AF XY:

0.0199

AC XY:

14450

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.116

AC:

3890

AN:

33474

American (AMR)

AF:

0.0537

AC:

2400

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2819

AN:

26122

East Asian (EAS)

AF:

0.000554

AC:

AN:

39700

South Asian (SAS)

AF:

0.00468

AC:

404

AN:

86252

European-Finnish (FIN)

AF:

0.00217

AC:

116

AN:

53416

Middle Eastern (MID)

AF:

0.0479

AC:

276

AN:

5766

European-Non Finnish (NFE)

AF:

0.0165

AC:

18306

AN:

1111972

Other (OTH)

AF:

0.0322

AC:

1943

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

1521

3041

4562

6082

7603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

746

1492

2238

2984

3730

<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:

0.0492

AC:

7485

AN:

152222

Hom.:

341

Cov.:

AF XY:

0.0468

AC XY:

3483

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.115

AC:

4758

AN:

41500

American (AMR)

AF:

0.0546

AC:

834

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

378

AN:

3470

East Asian (EAS)

AF:

0.00231

AC:

AN:

5186

South Asian (SAS)

AF:

0.00456

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0191

AC:

1299

AN:

68020

Other (OTH)

AF:

0.0696

AC:

147

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

339

679

1018

1358

1697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0320

Hom.:

645

Bravo

AF:

0.0573

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.116

AC:

510

ESP6500EA

AF:

0.0217

AC:

187

ExAC

AF:

0.0289

AC:

3508

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0242

EpiControl

AF:

0.0260

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MSH5-related disorder

Benign:1

Oct 17, 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

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.075

T;T;.;.;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.66

MetaRNN

Benign

0.0015

T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.0

M;M;.;.;.;.

PhyloP100

1.0

PROVEAN

Benign

-0.54

N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.19

T;T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;T;T

Polyphen

0.31

B;B;B;B;.;.

Vest4

0.099

MPC

0.59

ClinPred

0.0073

GERP RS

4.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.038

gMVP

0.34

Mutation Taster

=98/2

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

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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