MDM4

MDM4 regulator of p53, the group of Ring finger proteins

Basic information

Region (hg38): 1:204516378-204558120

Links

ENSG00000198625 ∙ NCBI:4194 ∙ OMIM:602704 ∙ HGNC:6974 ∙ Uniprot:O15151 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• bone marrow failure syndrome 6 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Bone marrow failure syndrome 6	AD	Hematologic; Oncologic	Individuals (including based on family history) have been described with bone marrow failure as well as apparent increased risk of malignancies, and awareness may allow prompt management	Hematologic; Oncologic	32300648

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MDM4 gene.

• not provided (11 variants)
• Inborn genetic diseases (9 variants)
• Bone marrow failure syndrome 6 (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MDM4 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	4
missense			13	2	1	16
nonsense						0
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding						0
Total	0	0	14	4	3

Variants in MDM4

This is a list of pathogenic ClinVar variants found in the MDM4 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-204525540-G-A			Benign (Jul 10, 2018)
1-204525580-C-G		not specified	Uncertain significance (Jan 30, 2024)
1-204526376-C-T			Likely benign (Aug 01, 2022)
1-204526377-G-A			Likely benign (Apr 01, 2023)
1-204530752-A-T			Benign/Likely benign (Jan 01, 2023)
1-204538279-C-T		not specified	Uncertain significance (Dec 21, 2023)
1-204538306-A-G		not specified	Uncertain significance (Aug 17, 2022)
1-204538313-G-A			Benign (Mar 29, 2018)
1-204542808-C-G		not specified	Uncertain significance (Jun 29, 2022)
1-204542898-A-G		not specified	Uncertain significance (Apr 06, 2023)
1-204544563-C-T		not specified	Uncertain significance (Jul 16, 2021)
1-204544596-T-C		MDM4-related disorder • not specified	Conflicting classifications of pathogenicity (Jan 02, 2024)
1-204544611-G-A		not specified	Uncertain significance (Feb 10, 2023)
1-204544640-A-G		not specified	Uncertain significance (Jan 04, 2022)
1-204546797-G-T		not specified	Uncertain significance (Dec 15, 2023)
1-204549118-G-A			Benign (Mar 05, 2018)
1-204549153-C-T		not specified	Uncertain significance (Jan 30, 2024)
1-204549254-A-G		Bone marrow failure syndrome 6	Uncertain significance (May 14, 2021)
1-204549275-G-A		not specified	Uncertain significance (Jul 13, 2022)
1-204549286-C-A			Likely benign (Dec 01, 2023)
1-204549295-TC-T			Uncertain significance (Aug 01, 2021)
1-204549329-A-C			Likely benign (Feb 01, 2024)
1-204549344-A-C		not specified	Uncertain significance (Jun 24, 2022)
1-204549356-T-C		Bone marrow failure syndrome 6	Uncertain significance (Jan 03, 2022)
1-204549402-C-T		not specified	Uncertain significance (Apr 22, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MDM4	protein_coding	protein_coding	ENST00000367182	10	57361

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000812	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.71	181	259	0.700	0.0000126	3230
Missense in Polyphen		33	83.031	0.39744		1066
Synonymous	-0.723	101	92.2	1.10	0.00000493	894
Loss of Function	4.79	0	26.7	0.00	0.00000139	326

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions. {ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:16511572}.
• Pathway: p53 signaling pathway - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Signaling Pathways in Glioblastoma;Gene expression (Transcription);Generic Transcription Pathway;Oncogene Induced Senescence;Oxidative Stress Induced Senescence;Cellular Senescence;Cellular responses to stress;Post-translational protein modification;Metabolism of proteins;RNA Polymerase II Transcription;Stabilization of p53;p53-Dependent G1 DNA Damage Response;p53-Dependent G1/S DNA damage checkpoint;G1/S DNA Damage Checkpoints;Cell Cycle Checkpoints;Cellular responses to external stimuli;Ub-specific processing proteases;Regulation of TP53 Degradation;Regulation of TP53 Expression and Degradation;Deubiquitination;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity through Methylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Cell Cycle;p53 pathway (Consensus)

Recessive Scores

• pRec: 0.160

Intolerance Scores

• loftool: 0.501
• rvis_EVS: 0.08
• rvis_percentile_EVS: 60.31

Haploinsufficiency Scores

• pHI: 0.836
• hipred: Y
• hipred_score: 0.802
• ghis: 0.516

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mdm4
• Phenotype: muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism 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; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); endocrine/exocrine gland phenotype; neoplasm; pigmentation phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; immune system phenotype; renal/urinary system phenotype; embryo phenotype; liver/biliary system 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)

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest;cell population proliferation;negative regulation of cell population proliferation;protein ubiquitination;protein deubiquitination;DNA damage response, signal transduction by p53 class mediator;negative regulation of protein catabolic process;negative regulation of apoptotic process;G0 to G1 transition;protein stabilization;protein-containing complex assembly;negative regulation of cell cycle arrest;cellular response to hypoxia;regulation of signal transduction by p53 class mediator
• Cellular component: nucleus;nucleoplasm
• Molecular function: protein binding;zinc ion binding;enzyme binding;ubiquitin protein ligase activity