Genetic Variant MSH4:p.Cys72Tyr (chr1-75797200-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002440.4(MSH4):c.215G>A(p.Cys72Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,606,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MSH4
NM_002440.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.122

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014898986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4 link	c.215G>A	p.Cys72Tyr	missense_variant	Exon 1 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.215G>A	p.Cys72Tyr	missense_variant	Exon 1 of 20	1	NM_002440.4	ENSP00000263187.3		O15457

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000651

AC:

AN:

230412

AF XY:

0.0000398

show subpopulations

Gnomad AFR exome

AF:

0.000893

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1454502

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

722920

show subpopulations

African (AFR)

AF:

0.000599

AC:

AN:

33394

American (AMR)

AF:

0.0000230

AC:

AN:

43410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25932

East Asian (EAS)

AF:

0.00

AC:

AN:

39506

South Asian (SAS)

AF:

0.0000939

AC:

AN:

85228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108800

Other (OTH)

AF:

0.0000166

AC:

AN:

60082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000151

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.215G>A (p.C72Y) alteration is located in exon 1 (coding exon 1) of the MSH4 gene. This alteration results from a G to A substitution at nucleotide position 215, causing the cysteine (C) at amino acid position 72 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.38

CADD

Benign

2.4

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.050

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.40

M_CAP

Benign

0.023

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.55

PhyloP100

0.12

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

REVEL

Benign

0.27

Sift

Benign

0.62

Sift4G

Uncertain

0.041

Polyphen

0.0010

Vest4

0.14

MVP

0.40

MPC

0.12

ClinPred

0.012

GERP RS

-7.2

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.047

gMVP

0.30

Mutation Taster

=98/2

polymorphism

(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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1-75797200-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