Variant 1-75803775-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 -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/exons	MANE	Protein	UniProt
MSH4	NM_002440.4 linkuse as main transcript	c.289G>A	p.Ala97Thr	missense_variant	2/20	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.289G>A	p.Ala97Thr	missense_variant	2/20	1	NM_002440.4	ENSP00000263187	P1

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

GnomAD3 exomes

AF:

0.260

AC:

61701

AN:

236992

Hom.:

9028

AF XY:

0.263

AC XY:

33625

AN XY:

128050

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 SAS exome

AF:

0.216

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

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.190

Gnomad4 ASJ exome

AF:

0.429

Gnomad4 EAS exome

AF:

0.0379

Gnomad4 SAS exome

AF:

0.220

Gnomad4 FIN exome

AF:

0.325

Gnomad4 NFE exome

AF:

0.281

Gnomad4 OTH exome

AF:

0.276

GnomAD4 genome

AF:

0.277

AC:

42069

AN:

152004

Hom.:

6119

Cov.:

AF XY:

0.275

AC XY:

20448

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.297

Gnomad4 AMR

AF:

0.233

Gnomad4 ASJ

AF:

0.443

Gnomad4 EAS

AF:

0.0268

Gnomad4 SAS

AF:

0.213

Gnomad4 FIN

AF:

0.319

Gnomad4 NFE

AF:

0.284

Gnomad4 OTH

AF:

0.302

Alfa

AF:

0.291

Hom.:

17323

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Premature ovarian failure 20

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

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

MutationTaster

Benign

1.0

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over