MUS81

protein-coding

MUS81 structure-specific endonuclease subunit

Gene summary

This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

MANE transcript

NM_025128.5

Inheritance

—

ClinVar variants

U:102B:7

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr11:65,857,126-65,867,653

External References & Databases

Ensembl (ENSG00000172732)

Transcript & Mutation Effects

hg38 • Region Span ~10.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MUS81 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 92

not providedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025128.5. 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	2 clinvar		5
missense			93 clinvar	3 clinvar	2 clinvar	98
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	102	5	2	109

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025128.5	RefSeq	NP_079404.3	16	MANE Select
ENST00000308110.9	Ensembl	ENSP00000307853.4	16	MANE Select
NM_001350283.2	RefSeq	NP_001337212.1	16	Standard
ENST00000524647.5	Ensembl	ENSP00000433473.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
Homologous recombination - Homo sapiens (human)
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
Fanconi Anemia Pathway
DNA Repair

Biological Process

resolution of meiotic recombination intermediates
double-strand break repair via break-induced replication
DNA catabolic process, endonucleolytic
DNA repair
intra-S DNA damage checkpoint

Molecular Function

DNA binding
endodeoxyribonuclease activity
protein binding
crossover junction endodeoxyribonuclease activity
metal ion binding

Cellular Component

nucleus
nucleoplasm
nucleolus
Holliday junction resolvase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308110
Coding exons: 16
Length: 10528
Individuals with no LoFs: 125655
Homozygous LoFs: 0
Heterozygous LoFs: 93
Defined: 125748
p: 0.000370

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0565	331	334	0.991	0.0000194	3444
Missense (PolyPhen)		65	81.122	0.80126		873
Synonymous	0.429	134	140	0.954	0.00000779	1194
Loss of Function	1.62	24	34.2	0.701	0.00000188	345

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.00055	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Interacts with EME1 and EME2 to form a DNA structure- specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. Typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. May be required in mitosis for the processing of stalled or collapsed replication forks. {ECO:0000269|PubMed:11741546, ECO:0000269|PubMed:12374758, ECO:0000269|PubMed:12686547, ECO:0000269|PubMed:12721304, ECO:0000269|PubMed:14617801, ECO:0000269|PubMed:15805243, ECO:0000269|PubMed:17289582, ECO:0000269|PubMed:19595721, ECO:0000269|PubMed:19596235}.;

Recessive Scores

pRec: 0.187

Intolerance Scores

LoFtool: 0.883
RVIS EVS: 0.78
RVIS percentile EVS: 87.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.271

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High