Genetic Variant MSH4:p.Ala97Thr (chr1-75803775-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002440.4(MSH4):c.289G>A(p.Ala97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,597,556 control chromosomes in the GnomAD database, including 62,527 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.28 ( 6119 hom., cov: 32)

Exomes 𝑓: 0.27 ( 56408 hom. )

Consequence

MSH4
NM_002440.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.864

Publications

42 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055417717).

BP6

Variant 1-75803775-G-A is Benign according to our data. Variant chr1-75803775-G-A is described in ClinVar as [Benign]. Clinvar id is 2585667.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4 link	c.289G>A	p.Ala97Thr	missense_variant	Exon 2 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.289G>A	p.Ala97Thr	missense_variant	Exon 2 of 20	1	NM_002440.4	ENSP00000263187.3		O15457

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42055

AN:

151886

Hom.:

6118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.443

Gnomad EAS

AF:

0.0265

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.319

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.260

AC:

61701

AN:

236992

AF XY:

0.263

show subpopulations

Gnomad AFR exome

AF:

0.304

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.423

Gnomad EAS exome

AF:

0.0185

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.296

Gnomad OTH exome

AF:

0.303

GnomAD4 exome

AF:

0.273

AC:

394433

AN:

1445552

Hom.:

56408

Cov.:

AF XY:

0.273

AC XY:

196206

AN XY:

718640

show subpopulations

African (AFR)

AF:

0.309

AC:

10061

AN:

32590

American (AMR)

AF:

0.190

AC:

7827

AN:

41250

Ashkenazi Jewish (ASJ)

AF:

0.429

AC:

10977

AN:

25616

East Asian (EAS)

AF:

0.0379

AC:

1482

AN:

39086

South Asian (SAS)

AF:

0.220

AC:

18068

AN:

82296

European-Finnish (FIN)

AF:

0.325

AC:

17298

AN:

53206

Middle Eastern (MID)

AF:

0.326

AC:

1861

AN:

5706

European-Non Finnish (NFE)

AF:

0.281

AC:

310390

AN:

1106048

Other (OTH)

AF:

0.276

AC:

16469

AN:

59754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

12637

25275

37912

50550

63187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.277

AC:

42069

AN:

152004

Hom.:

6119

Cov.:

AF XY:

0.275

AC XY:

20448

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.297

AC:

12313

AN:

41428

American (AMR)

AF:

0.233

AC:

3564

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

1535

AN:

3468

East Asian (EAS)

AF:

0.0268

AC:

139

AN:

5188

South Asian (SAS)

AF:

0.213

AC:

1026

AN:

4826

European-Finnish (FIN)

AF:

0.319

AC:

3361

AN:

10534

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.284

AC:

19292

AN:

67954

Other (OTH)

AF:

0.302

AC:

639

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1559

3119

4678

6238

7797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.286

Hom.:

32577

Bravo

AF:

0.274

TwinsUK

AF:

0.258

AC:

958

ALSPAC

AF:

0.297

AC:

1146

ESP6500AA

AF:

0.300

AC:

1324

ESP6500EA

AF:

0.299

AC:

2572

ExAC

AF:

0.262

AC:

31826

Asia WGS

AF:

0.140

AC:

488

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spermatogenic failure 2

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Premature ovarian failure 20

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.3

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.022

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.86

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.28

REVEL

Benign

0.13

Sift

Benign

0.18

Sift4G

Benign

0.39

Polyphen

0.0010

Vest4

0.021

MPC

0.068

ClinPred

0.0058

GERP RS

0.63

Varity_R

0.040

gMVP

0.36

Mutation Taster

=97/3

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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1-75803775-G-A

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