MCM8

protein-coding

minichromosome maintenance 8 homologous recombination repair factor, the group of MCM family

Gene summary

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the mini-chromosome maintenance proteins is a key component of the pre-replication complex and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein contains the central domain that is conserved among the mini-chromosome maintenance proteins. The encoded protein may interact with other mini-chromosome maintenance proteins and play a role in DNA replication. This gene may be associated with length of reproductive lifespan and menopause. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

Previous symbols:

C20orf154

MANE transcript

NM_032485.6

Inheritance

AR, AD

ClinVar variants

P:19U:118B:24

Top phenotype

Premature ovarian failure 10

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr20:5,950,652-5,998,977

External References & Databases

Ensembl (ENSG00000125885)

Transcript & Mutation Effects

hg38 • Region Span ~48.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

premature ovarian failure 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044776

Submitter: Ambry Genetics

premature ovarian failure 10LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0044776

Submitter: Ambry Genetics

colorectal cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005575

Submitter: Ambry Genetics

premature ovarian failure 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044776

Submitter: Labcorp Genetics (formerly Invitae)

premature ovarian failure 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044776

Submitter: Ambry Genetics

premature ovarian failure 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044776

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Premature ovarian failure 10AR

Manifestation: Endocrine; Obstetric

Intervention: Endocrine

Rationale: Individuals have been described with manifestations including hypothyroidism and hypergonadotropic hypogonadism, and response to hormonal therapy has been described as being beneficial

Comments: Unlike some other forms of Premature ovarian failure, measures to allow fertility through egg preservation may not be helpful

Refs: 25437880; 25873734

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCM8 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 106

not providedTotal: 21

Premature ovarian failure 10Total: 15

MCM8-related disorderTotal: 9

MCM8-related disordersTotal: 3

not specifiedTotal: 3

AzoospermiaTotal: 1

Joubert syndrome 6Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032485.6. 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				6 clinvar	2 clinvar	8
missense	1 clinvar	3 clinvar	112 clinvar	7 clinvar	9 clinvar	132
nonsense	2 clinvar	3 clinvar	2 clinvar			7
start loss						0
frameshift	4 clinvar	2 clinvar				6
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	4 clinvar			8
Total	8	11	118	13	11	161

Highest pathogenic variant AF is 0.000055882338

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032485.6	RefSeq	NP_115874.3	18	MANE Select
ENST00000610722.4	Ensembl	ENSP00000478141.1	18	MANE Select
NM_001281520.2	RefSeq	NP_001268449.1	18	Standard
NM_001281521.2	RefSeq	NP_001268450.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell Cycle
Activation of ATR in response to replication stress
G2/M Checkpoints
Cell Cycle Checkpoints
Activation of the pre-replicative complex

Biological Process

G1/S transition of mitotic cell cycle
double-strand break repair via homologous recombination
DNA replication
cellular response to DNA damage stimulus
female gamete generation

Molecular Function

DNA binding
chromatin binding
helicase activity
protein binding
ATP binding

Cellular Component

nucleus
nucleoplasm
chromosome
MCM8-MCM9 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378896
Coding exons: 18
Length: 44555
Individuals with no LoFs: 125606
Homozygous LoFs: 0
Heterozygous LoFs: 142
Defined: 125748
p: 0.000565

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.357	426	447	0.953	0.0000228	5483
Missense (PolyPhen)		149	179.28	0.83109		2176
Synonymous	0.295	148	153	0.970	0.00000758	1607
Loss of Function	1.85	32	45.5	0.704	0.00000256	550

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00082	0.00081	rare
Ashkenazi Jewish	0.00050	0.00030	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00063	0.00062	rare
South Asian	0.00064	0.00062	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). Required for DNA resection by the MRE11-RAD50- NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity (PubMed:26215093). Probably by regulating the localization of the MNR complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). However, may play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC) (PubMed:15684404). Probably by regulating HR, plays a key role during gametogenesis (By similarity). Stabilizes MCM9 protein (PubMed:23401855, PubMed:26215093). {ECO:0000250|UniProtKB:Q9CWV1, ECO:0000269|PubMed:15684404, ECO:0000269|PubMed:23401855, ECO:0000269|PubMed:26215093}.;
Disease: DISEASE: Premature ovarian failure 10 (POF10) [MIM:612885]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:25437880}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.198

Intolerance Scores

LoFtool: 0.997
RVIS EVS: 1.41
RVIS percentile EVS: 94.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.986

Gene Damage Prediction

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