Variant rs5745549 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MSH4	NM_002440.4 linkuse as main transcript	c.2741G>A	p.Ser914Asn	missense_variant	20/20	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4 linkuse as main transcript	c.2741G>A	p.Ser914Asn	missense_variant	20/20	1	NM_002440.4	ENSP00000263187	P1

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

GnomAD3 exomes

AF:

0.0403

AC:

9231

AN:

229014

Hom.:

277

AF XY:

0.0387

AC XY:

4820

AN XY:

124530

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 SAS exome

AF:

0.0314

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

Gnomad4 AFR exome

AF:

0.127

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.0298

Gnomad4 EAS exome

AF:

0.00600

Gnomad4 SAS exome

AF:

0.0301

Gnomad4 FIN exome

AF:

0.0595

Gnomad4 NFE exome

AF:

0.0370

Gnomad4 OTH exome

AF:

0.0423

GnomAD4 genome

AF:

0.0669

AC:

10158

AN:

151870

Hom.:

490

Cov.:

AF XY:

0.0661

AC XY:

4911

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.0457

Gnomad4 ASJ

AF:

0.0317

Gnomad4 EAS

AF:

0.00541

Gnomad4 SAS

AF:

0.0328

Gnomad4 FIN

AF:

0.0596

Gnomad4 NFE

AF:

0.0407

Gnomad4 OTH

AF:

0.0585

Alfa

AF:

0.0417

Hom.:

374

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

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

MutationTaster

Benign

1.0

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over