MSH4

mutS homolog 4, the group of MutS homologs

Basic information

Region (hg38): 1:75796881-75913242

Links

ENSG00000057468 ∙ NCBI:4438 ∙ OMIM:602105 ∙ HGNC:7327 ∙ Uniprot:O15457 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• premature ovarian failure 20 (Strong), mode of inheritance: AR
• premature ovarian failure 20 (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Premature ovarian failure 20	AR	Obstetric	Genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency	Endocrine; Genitourinary; Obstetric	28541421; 33437391; 33448284; 34755185; 35090489

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MSH4 gene.

• Inborn genetic diseases (25 variants)
• Spermatogenic failure 2 (7 variants)
• Premature ovarian failure 20 (7 variants)
• not provided (4 variants)
• Non-obstructive azoospermia (4 variants)
• Premature ovarian insufficiency (1 variants)
• Oligospermia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MSH4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous					2	2
missense		1	26	1	2	30
nonsense		2				2
start loss						0
frameshift		1				1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					2	2
non coding					1	1
Total	0	4	26	1	5

Highest pathogenic variant AF is 0.000164

Variants in MSH4

This is a list of pathogenic ClinVar variants found in the MSH4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-75797008-C-T		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
1-75797022-G-A		Inborn genetic diseases	Uncertain significance (Nov 09, 2021)
1-75797026-C-T		Inborn genetic diseases	Uncertain significance (Dec 11, 2023)
1-75797041-C-T		Inborn genetic diseases	Uncertain significance (Feb 05, 2024)
1-75797056-G-T			Uncertain significance (Oct 01, 2023)
1-75797074-G-C		Inborn genetic diseases	Uncertain significance (Aug 22, 2023)
1-75797074-G-T		Inborn genetic diseases	Uncertain significance (Oct 29, 2021)
1-75797077-A-G		Inborn genetic diseases	Uncertain significance (Nov 07, 2022)
1-75797088-C-A		Inborn genetic diseases	Uncertain significance (Dec 21, 2022)
1-75797105-G-T		Inborn genetic diseases	Uncertain significance (Nov 30, 2021)
1-75797152-C-T		Inborn genetic diseases	Uncertain significance (Sep 27, 2022)
1-75797200-G-A		Inborn genetic diseases	Uncertain significance (Jan 08, 2024)
1-75797208-C-A		Inborn genetic diseases	Uncertain significance (May 31, 2023)
1-75803731-G-C		Inborn genetic diseases	Uncertain significance (Jan 24, 2023)
1-75803775-G-A		Spermatogenic failure 2 • Premature ovarian failure 20	Benign (Apr 11, 2023)
1-75803889-T-C		Inborn genetic diseases	Uncertain significance (Jan 04, 2024)
1-75807039-A-T		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
1-75807093-C-A		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
1-75810733-A-G		Inborn genetic diseases	Uncertain significance (Nov 07, 2022)
1-75810755-G-T		Inborn genetic diseases	Uncertain significance (Dec 26, 2023)
1-75815059-T-A		Inborn genetic diseases	Uncertain significance (Jul 12, 2022)
1-75815081-A-G		Inborn genetic diseases	Uncertain significance (Mar 31, 2023)
1-75815125-GGTTCAGTC-G		Spermatogenic failure 2	Pathogenic (Jul 01, 2022)
1-75816435-T-C		Inborn genetic diseases	Uncertain significance (Feb 05, 2024)
1-75816482-A-G		Inborn genetic diseases	Uncertain significance (Dec 21, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MSH4	protein_coding	protein_coding	ENST00000263187	20	116357

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.12e-18	0.313	125622	0	126	125748	0.000501

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.806	413	462	0.894	0.0000228	6029
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00111	0.00106
Ashkenazi Jewish	0.00256	0.00248
East Asian	0.000184	0.000163
Finnish	0.000327	0.000277
European (Non-Finnish)	0.000550	0.000528
Middle Eastern	0.000184	0.000163
South Asian	0.000326	0.000294
Other	0.000353	0.000326

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.454
• hipred: N
• hipred_score: 0.457
• ghis: 0.447

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.801

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Msh4
• Phenotype: reproductive system phenotype; cellular phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: resolution of meiotic recombination intermediates;ovarian follicle development;mismatch repair;reciprocal meiotic recombination;spermatogenesis;female gamete generation;homologous chromosome segregation;chiasma assembly
• Cellular component: nuclear chromosome;synaptonemal complex;nucleus;recombination nodule;mismatch repair complex
• Molecular function: DNA binding;damaged DNA binding;protein binding;ATP binding;DNA-dependent ATPase activity;guanine/thymine mispair binding;single thymine insertion binding