dbSNP rs5745549: MSH4:p.Ser914Asn (chr1-75912817-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002440.4(MSH4):c.2741G>A(p.Ser914Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,586,522 control chromosomes in the GnomAD database, including 1,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.067 ( 490 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1332 hom. )

Consequence

MSH4
NM_002440.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.636

Publications

24 publications found

Variant links:

Genes affected

MSH4 (HGNC:7327): (mutS homolog 4) This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair. [provided by RefSeq, Aug 2011]

MSH4 Gene-Disease associations (from GenCC):

premature ovarian failure 20
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

MSH4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015282333).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4 link	c.2741G>A	p.Ser914Asn	missense_variant	Exon 20 of 20	ENST00000263187.4	NP_002431.2	O15457

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4 link	c.2741G>A	p.Ser914Asn	missense_variant	Exon 20 of 20	1	NM_002440.4	ENSP00000263187.3		O15457

Frequencies

GnomAD3 genomes

AF:

0.0667

AC:

10116

AN:

151752

Hom.:

482

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.134

Gnomad AMR

AF:

0.0458

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.00540

Gnomad SAS

AF:

0.0332

Gnomad FIN

AF:

0.0596

Gnomad MID

AF:

0.0256

Gnomad NFE

AF:

0.0407

Gnomad OTH

AF:

0.0596

GnomAD2 exomes

AF:

0.0403

AC:

9231

AN:

229014

AF XY:

0.0387

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.0230

Gnomad ASJ exome

AF:

0.0292

Gnomad EAS exome

AF:

0.00610

Gnomad FIN exome

AF:

0.0593

Gnomad NFE exome

AF:

0.0385

Gnomad OTH exome

AF:

0.0359

GnomAD4 exome

AF:

0.0385

AC:

55180

AN:

1434652

Hom.:

1332

Cov.:

AF XY:

0.0382

AC XY:

27273

AN XY:

713428

show subpopulations

African (AFR)

AF:

0.127

AC:

4042

AN:

31776

American (AMR)

AF:

0.0263

AC:

1067

AN:

40616

Ashkenazi Jewish (ASJ)

AF:

0.0298

AC:

764

AN:

25636

East Asian (EAS)

AF:

0.00600

AC:

224

AN:

37346

South Asian (SAS)

AF:

0.0301

AC:

2471

AN:

82064

European-Finnish (FIN)

AF:

0.0595

AC:

3149

AN:

52918

Middle Eastern (MID)

AF:

0.0465

AC:

265

AN:

5694

European-Non Finnish (NFE)

AF:

0.0370

AC:

40699

AN:

1099466

Other (OTH)

AF:

0.0423

AC:

2499

AN:

59136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2304

4608

6912

9216

11520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1542

3084

4626

6168

7710

<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:

0.0669

AC:

10158

AN:

151870

Hom.:

490

Cov.:

AF XY:

0.0661

AC XY:

4911

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.133

AC:

5521

AN:

41398

American (AMR)

AF:

0.0457

AC:

697

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3466

East Asian (EAS)

AF:

0.00541

AC:

AN:

5174

South Asian (SAS)

AF:

0.0328

AC:

158

AN:

4816

European-Finnish (FIN)

AF:

0.0596

AC:

627

AN:

10520

Middle Eastern (MID)

AF:

0.0241

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0407

AC:

2765

AN:

67954

Other (OTH)

AF:

0.0585

AC:

123

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

465

930

1396

1861

2326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0450

Hom.:

843

Bravo

AF:

0.0676

TwinsUK

AF:

0.0421

AC:

156

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.126

AC:

553

ESP6500EA

AF:

0.0400

AC:

344

ExAC

AF:

0.0436

AC:

5292

Asia WGS

AF:

0.0340

AC:

116

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.033

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PhyloP100

0.64

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.73

REVEL

Benign

0.21

Sift

Benign

0.38

Sift4G

Benign

0.18

Polyphen

0.41

Vest4

0.033

MPC

0.066

ClinPred

0.014

GERP RS

-0.34

Varity_R

0.055

gMVP

0.21

Mutation Taster

=99/1

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

Computational scores

Splicing

Publications

Other links and lift over