MCM4

minichromosome maintenance complex component 4, the group of MCM family|minichromosome maintenance 2-7 complex

Basic information

Region (hg38): 8:47960184-47978160

Previous symbols: [ "CDC21" ]

Links

ENSG00000104738 ∙ NCBI:4173 ∙ OMIM:602638 ∙ HGNC:6947 ∙ Uniprot:P33991 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (Supportive), mode of inheritance: AR
• primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (Strong), mode of inheritance: AR
• primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 54	AR	Allergy/Immunology/Infectious; Endocrine; Oncologic	Individuals are susceptible to recurrent infections, and early and aggressive management may be beneficial related to morbidity and mortality; Adrenal insufficiency has been described, and medical management (with corticosteroids) has been described; Individuals have been suggested to have susceptibility to cancer, and awareness may allow early detection and management	Allergy/Immunology/Infectious; Endocrine; Musculoskeletal; Oncologic	14702466; 17142786; 22354167; 22354170

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MCM4 gene.

• not provided (411 variants)
• Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency (112 variants)
• Inborn genetic diseases (26 variants)
• not specified (2 variants)
• MCM4-related condition (1 variants)
• Microcephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MCM4 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			4	91	2	97
missense			218	5	1	224
nonsense		1	3			4
start loss						0
frameshift			5			5
inframe indel			3			3
splice donor/acceptor (+/-2bp)	1		4			5
splice region			12	15	4	31
non coding			35	55	13	103
Total	1	1	272	151	16

Variants in MCM4

This is a list of pathogenic ClinVar variants found in the MCM4 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-47960391-G-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960399-CAA-C		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960423-A-AT		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960444-C-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960493-CG-C		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960644-A-G		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960666-A-G		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960672-G-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960692-T-C		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960701-A-C		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Benign (Jun 14, 2016)
8-47960738-G-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960773-G-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960798-C-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960818-T-TC		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960892-C-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960940-C-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jun 14, 2016)
8-47960952-G-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jan 12, 2018)
8-47960955-C-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jan 12, 2018)
8-47960961-G-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jan 13, 2018)
8-47960964-A-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Likely benign (Jan 13, 2018)
8-47960981-G-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jan 12, 2018)
8-47960996-A-G		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jan 13, 2018)
8-47961069-C-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jan 13, 2018)
8-47961081-G-A		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Uncertain significance (Jan 13, 2018)
8-47961090-C-T		Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MCM4	protein_coding	protein_coding	ENST00000262105	16	17976

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000146	1.00	125676	0	72	125748	0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.138	498	507	0.983	0.0000292	5651
Missense in Polyphen		142	185.23	0.76661		1964
Synonymous	-0.918	209	193	1.08	0.0000112	1712
Loss of Function	3.78	14	39.7	0.353	0.00000200	465

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000521	0.000509
Ashkenazi Jewish	0.00	0.00
East Asian	0.000980	0.000979
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000276	0.000273
Middle Eastern	0.000980	0.000979
South Asian	0.000239	0.000229
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. {ECO:0000269|PubMed:16899510, ECO:0000269|PubMed:9305914}.
• Disease: DISEASE: Immunodeficiency 54 (IMD54) [MIM:609981]: An autosomal recessive disorder characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. {ECO:0000269|PubMed:22354167, ECO:0000269|PubMed:22354170, ECO:0000269|PubMed:22499342}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cell cycle - Homo sapiens (human);DNA replication - Homo sapiens (human);Cell Cycle;Gastric Cancer Network 1;Retinoblastoma (RB) in Cancer;G1 to S cell cycle control;DNA Replication;cdk regulation of dna replication;Activation of ATR in response to replication stress;G2/M Checkpoints;Cell Cycle Checkpoints;Activation of the pre-replicative complex;Unwinding of DNA;Mitotic G1-G1/S phases;Orc1 removal from chromatin;DNA Replication;Switching of origins to a post-replicative state;DNA strand elongation;Synthesis of DNA;S Phase;G1/S Transition;C-MYB transcription factor network;Assembly of the pre-replicative complex;DNA Replication Pre-Initiation;M/G1 Transition;Cell Cycle;Cell Cycle, Mitotic (Consensus)

Recessive Scores

• pRec: 0.155

Intolerance Scores

• loftool: 0.813
• rvis_EVS: -1.1
• rvis_percentile_EVS: 6.89

Haploinsufficiency Scores

• pHI: 0.953
• hipred: Y
• hipred_score: 0.648
• ghis: 0.707

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.992

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mcm4
• Phenotype: cellular phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; digestive/alimentary phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; neoplasm; embryo phenotype

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;DNA replication;DNA unwinding involved in DNA replication;DNA replication initiation
• Cellular component: nuclear chromosome, telomeric region;nucleus;nucleoplasm;membrane;MCM complex
• Molecular function: single-stranded DNA binding;ATP-dependent DNA helicase activity;protein binding;ATP binding