Genetic Variant MSH4:p.Ala148Ala (chr1-75806997-G-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_002440.4(MSH4):c.444G>T(p.Ala148Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,570,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

MSH4
NM_002440.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0740

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 1-75806997-G-T is Benign according to our data. Variant chr1-75806997-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3777934.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.074 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4 link	c.444G>T	p.Ala148Ala	synonymous_variant	Exon 3 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.444G>T	p.Ala148Ala	synonymous_variant	Exon 3 of 20	1	NM_002440.4	ENSP00000263187.3		O15457

Frequencies

GnomAD3 genomes

AF:

0.000448

AC:

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000824

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000466

AC:

AN:

212424

AF XY:

0.000431

show subpopulations

Gnomad AFR exome

AF:

0.000216

Gnomad AMR exome

AF:

0.000338

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000190

Gnomad NFE exome

AF:

0.000816

Gnomad OTH exome

AF:

0.000200

GnomAD4 exome

AF:

0.000589

AC:

835

AN:

1418268

Hom.:

Cov.:

AF XY:

0.000531

AC XY:

374

AN XY:

704392

show subpopulations

African (AFR)

AF:

0.0000653

AC:

AN:

30610

American (AMR)

AF:

0.000264

AC:

AN:

34064

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

25010

East Asian (EAS)

AF:

0.00

AC:

AN:

37000

South Asian (SAS)

AF:

0.00

AC:

AN:

76190

European-Finnish (FIN)

AF:

0.000151

AC:

AN:

53038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.000709

AC:

779

AN:

1097978

Other (OTH)

AF:

0.000613

AC:

AN:

58704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000448

AC:

AN:

151924

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41424

American (AMR)

AF:

0.000131

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000824

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000518

Hom.:

Bravo

AF:

0.000431

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MSH4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

3.2

(source)

DANN

Benign

0.40

PhyloP100

-0.074

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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chr1-75806997-G-T

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