Genetic Variant MSH4:p.Pro75Ser (chr1-75797208-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002440.4(MSH4):c.223C>T(p.Pro75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,430 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P75T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MSH4
NM_002440.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.172

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10266107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4 link	c.223C>T	p.Pro75Ser	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.223C>T	p.Pro75Ser	missense_variant	Exon 1 of 20	1	NM_002440.4	ENSP00000263187.3		O15457

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453430

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

43180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39480

South Asian (SAS)

AF:

0.00

AC:

AN:

85082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108338

Other (OTH)

AF:

0.00

AC:

AN:

60052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

3.9

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.028

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.45

M_CAP

Benign

0.039

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.34

PhyloP100

0.17

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.73

REVEL

Benign

0.23

Sift

Benign

0.24

Sift4G

Benign

0.66

Polyphen

0.084

Vest4

0.21

MutPred

0.14

Gain of phosphorylation at P75 (P = 0.0111);

MVP

0.65

MPC

0.071

ClinPred

0.24

GERP RS

2.8

PromoterAI

0.045

Neutral

(source)

Varity_R

0.038

gMVP

0.37

Mutation Taster

=93/7

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over