MSH4

protein-coding

mutS homolog 4, the group of MutS homologs

Gene summary

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]

MANE transcript

NM_002440.4

Inheritance

ClinVar variants

P:18U:133B:7

Top phenotype

Premature ovarian failure 20

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr1:75,796,882-75,913,242

External References & Databases

Ensembl (ENSG00000057468)

Transcript & Mutation Effects

hg38 • Region Span ~116.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

premature ovarian failure 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030975

Submitter: PanelApp Australia

premature ovarian failure 20LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030975

Submitter: Labcorp Genetics (formerly Invitae)

premature ovarian failure 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030975

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Premature ovarian failure 20AR

Manifestation: Endocrine; Genitourinary; Obstetric

Intervention: Obstetric

Rationale: Genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency

Refs: 28541421; 33437391; 33448284; 34755185; 35090489

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MSH4 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 127

not providedTotal: 12

Spermatogenic failure 2Total: 11

Premature ovarian failure 20Total: 7

Genetic non-acquired premature ovarian failureTotal: 6

Non-obstructive azoospermiaTotal: 4

MSH4-related conditionTotal: 4

Premature ovarian insufficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002440.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	1 clinvar		3
missense		5 clinvar	129 clinvar	4 clinvar	2 clinvar	140
nonsense	3 clinvar	2 clinvar				5
start loss						0
frameshift	3 clinvar	4 clinvar	2 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar					1
Total	7	11	133	5	2	158

Highest pathogenic variant AF is 0.00017129909

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002440.4	RefSeq	NP_002431.2	20	MANE Select
ENST00000263187.4	Ensembl	ENSP00000263187.3	20	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

resolution of meiotic recombination intermediates
ovarian follicle development
mismatch repair
reciprocal meiotic recombination
spermatogenesis

Molecular Function

DNA binding
damaged DNA binding
protein binding
ATP binding
DNA-dependent ATPase activity

Cellular Component

nuclear chromosome
synaptonemal complex
nucleus
recombination nodule
mismatch repair complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263187
Coding exons: 20
Length: 116357
Individuals with no LoFs: 125622
Homozygous LoFs: 0
Heterozygous LoFs: 126
Defined: 125748
p: 0.000501

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.806	413	462	0.894	0.0000228	6029
Missense (PolyPhen)		81	109.15	0.74212		1460
Synonymous	1.97	134	166	0.806	0.00000866	1761
Loss of Function	1.61	34	45.8	0.743	0.00000226	642

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00084	0.00080	rare
Latino/Admixed American	0.00026	0.00023	rare
Ashkenazi Jewish	0.0026	0.0025	notable
East Asian	0.00018	0.00016	rare
Finnish	0.00033	0.00028	rare
European (Non-Finnish)	0.00055	0.00053	rare
South Asian	0.00033	0.00029	rare
Other	0.00035	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in meiotic recombination. Required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis.;

Recessive Scores

pRec: 0.0945

Intolerance Scores

LoFtool: 0.173
RVIS EVS: 0.2
RVIS percentile EVS: 67.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium