MSH5

protein-coding

mutS homolog 5, the group of MutS homologs

Gene summary

This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

MANE transcript

NM_172166.4

Inheritance

ClinVar variants

P:13U:85B:11

Top phenotype

Premature ovarian failure 13

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr6:31,739,677-31,762,676

External References & Databases

Ensembl (ENSG00000204410)

Transcript & Mutation Effects

hg38 • Region Span ~23.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spermatogenic failure 74STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030972

Submitter: PanelApp Australia

spermatogenic failure 74STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030972

Submitter: Labcorp Genetics (formerly Invitae)

premature ovarian failure 13MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044317

Submitter: PanelApp Australia

premature ovarian failure 13LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0044317

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Premature ovarian failure 13AR

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: 28175301; 34755185

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MSH5 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 86

Premature ovarian failure 13Total: 11

Spermatogenic failure 74Total: 10

not providedTotal: 9

MSH5-related disorderTotal: 9

Non-obstructive azoospermiaTotal: 3

Genetic non-acquired premature ovarian failureTotal: 2

AzoospermiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_172166.4. 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				3 clinvar		3
missense	1 clinvar	2 clinvar	84 clinvar	7 clinvar	1 clinvar	95
nonsense		5 clinvar	1 clinvar			6
start loss						0
frameshift	3 clinvar	1 clinvar				4
splice donor/acceptor (+/-2bp)	1 clinvar					1
Total	5	8	85	10	1	109

Highest pathogenic variant AF is 0.00014341573

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_172166.4	RefSeq	NP_751898.1	24	MANE Select
ENST00000375750.9	Ensembl	ENSP00000364903.3	24	MANE Select
NM_002441.5	RefSeq	NP_002432.1	24	Standard
NM_025259.6	RefSeq	NP_079535.4	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ovarian Infertility Genes

Biological Process

mismatch repair
reciprocal meiotic recombination
homologous chromosome segregation
chiasma assembly

Molecular Function

damaged DNA binding
protein binding
ATP binding
DNA-dependent ATPase activity
guanine/thymine mispair binding

Cellular Component

mismatch repair complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375703
Coding exons: 24
Length: 24898
Individuals with no LoFs: 125550
Homozygous LoFs: 0
Heterozygous LoFs: 198
Defined: 125748
p: 0.000788

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.80	367	478	0.768	0.0000270	5432
Missense (PolyPhen)		87	128.74	0.6758		1470
Synonymous	2.22	146	184	0.792	0.0000104	1676
Loss of Function	3.30	26	51.6	0.504	0.00000312	529

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0013	notable
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0.00051	0.00050	rare
East Asian	0.00055	0.00054	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.00036	0.00036	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in DNA mismatch repair and meiotic recombination processes. Facilitates crossovers between homologs during meiosis (By similarity). {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.0416
RVIS EVS: 0.13
RVIS percentile EVS: 63.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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