ZMPSTE24

zinc metallopeptidase STE24, the group of M48 metallopeptidase family

Basic information

Region (hg38): 1:40258041-40294180

Links

ENSG00000084073 ∙ NCBI:10269 ∙ OMIM:606480 ∙ HGNC:12877 ∙ Uniprot:O75844 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mandibuloacral dysplasia with type B lipodystrophy (Strong), mode of inheritance: AR
• lethal restrictive dermopathy (Strong), mode of inheritance: AR
• mandibuloacral dysplasia with type B lipodystrophy (Moderate), mode of inheritance: AR
• lethal restrictive dermopathy (Supportive), mode of inheritance: AD
• Hutchinson-Gilford progeria syndrome (Supportive), mode of inheritance: AD
• mandibuloacral dysplasia with type B lipodystrophy (Supportive), mode of inheritance: AR
• mandibuloacral dysplasia with type B lipodystrophy (Strong), mode of inheritance: AR
• restrictive dermopathy 1 (Strong), mode of inheritance: AR
• mandibuloacral dysplasia with type B lipodystrophy (Definitive), mode of inheritance: AR
• lethal restrictive dermopathy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mandibuloacral dysplasia with type B lipodystrophy; Restrictive dermopathy 1	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Dental; Dermatologic; Musculoskeletal; Neurologic	1642279; 12913070; 15317753; 16297189; 15843403; 18435794; 19504603; 20034068; 22495976

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ZMPSTE24 gene.

• not provided (17 variants)
• Lethal tight skin contracture syndrome (6 variants)
• Mandibuloacral dysplasia with type B lipodystrophy (5 variants)
• Restrictive dermopathy 1 (3 variants)
• ZMPSTE24-related disorder (1 variants)
• Restrictive dermopathy 1;Mandibuloacral dysplasia with type B lipodystrophy (1 variants)
• Lethal tight skin contracture syndrome;Mandibuloacral dysplasia with type B lipodystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ZMPSTE24 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	24	3	29
missense	2		51	1		54
nonsense	9	2				11
start loss						0
frameshift	8	2				10
inframe indel		1				1
splice donor/acceptor (+/-2bp)	3	2	1			6
splice region	1		2	9	2	14
non coding			24	24	18	66
Total	22	7	78	49	21

Highest pathogenic variant AF is 0.000324

Variants in ZMPSTE24

This is a list of pathogenic ClinVar variants found in the ZMPSTE24 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-40258078-A-G			not provided (-)
1-40258087-C-G		Mandibuloacral dysplasia • Lethal tight skin contracture syndrome	Uncertain significance (Jun 14, 2016)
1-40258091-A-G		Lethal tight skin contracture syndrome • Mandibuloacral dysplasia	Uncertain significance (Jun 14, 2016)
1-40258100-A-C		Lethal tight skin contracture syndrome • Mandibuloacral dysplasia	Uncertain significance (Jun 14, 2016)
1-40258217-C-G		Mandibuloacral dysplasia • Lethal tight skin contracture syndrome	Uncertain significance (Jun 14, 2016)
1-40258226-G-A		Mandibuloacral dysplasia • Lethal tight skin contracture syndrome	Uncertain significance (Jun 14, 2016)
1-40258259-G-A		Mandibuloacral dysplasia with type B lipodystrophy • Lethal tight skin contracture syndrome	Uncertain significance (Jan 12, 2018)
1-40258279-T-C		not specified	Benign/Likely benign (Apr 10, 2024)
1-40258286-A-C			Likely benign (Oct 06, 2023)
1-40258288-C-T		Inborn genetic diseases	Uncertain significance (Jan 18, 2023)
1-40258290-C-T			Likely benign (Nov 28, 2022)
1-40258299-T-TA			Pathogenic (Jan 29, 2024)
1-40258301-G-T		Lethal tight skin contracture syndrome • Mandibuloacral dysplasia with type B lipodystrophy	Uncertain significance (Mar 23, 2022)
1-40258313-G-A			Likely benign (Jan 13, 2024)
1-40258319-GA-G		Lethal tight skin contracture syndrome	Pathogenic (Sep 01, 2021)
1-40258323-C-T		Mandibuloacral dysplasia with type B lipodystrophy • Lethal tight skin contracture syndrome	Uncertain significance (Jan 13, 2018)
1-40258324-G-GT		Lethal tight skin contracture syndrome	Pathogenic (Mar 17, 2022)
1-40258329-T-A			Uncertain significance (Dec 11, 2023)
1-40258331-C-T			Likely benign (Oct 19, 2022)
1-40258358-A-G			Likely benign (Jan 21, 2025)
1-40258366-T-G			Uncertain significance (Dec 20, 2021)
1-40258375-C-A			Uncertain significance (Mar 18, 2022)
1-40258392-C-T		Mandibuloacral dysplasia with type B lipodystrophy	Pathogenic (Jun 01, 2008)
1-40258402-T-C			Likely benign (Oct 08, 2022)
1-40260571-TA-T			Benign (Apr 17, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ZMPSTE24	protein_coding	protein_coding	ENST00000372759	10	36078

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.87e-16	0.0180	125670	0	78	125748	0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.372	228	244	0.933	0.0000116	3115
Missense in Polyphen		47	58.454	0.80405		724
Synonymous	0.911	77	87.9	0.876	0.00000397	893
Loss of Function	0.264	24	25.4	0.943	0.00000129	308

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000206	0.000206
Ashkenazi Jewish	0.000311	0.000298
East Asian	0.000272	0.000272
Finnish	0.000602	0.000601
European (Non-Finnish)	0.000309	0.000308
Middle Eastern	0.000272	0.000272
South Asian	0.000367	0.000359
Other	0.000815	0.000815

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Proteolytically removes the C-terminal three residues of farnesylated proteins. Acts on lamin A/C.
• Disease: DISEASE: Mandibuloacral dysplasia with type B lipodystrophy (MADB) [MIM:608612]: A disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of the cranial suture, joint contractures, and generalized lipodystrophy with loss of subcutaneous fat from the extremities, face, neck and trunk. {ECO:0000269|PubMed:12913070, ECO:0000269|PubMed:17152860, ECO:0000269|PubMed:18435794, ECO:0000269|PubMed:20814950}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lethal tight skin contracture syndrome (LTSCS) [MIM:275210]: Rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. {ECO:0000269|PubMed:15317753}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Terpenoid backbone biosynthesis - Homo sapiens (human);Adipogenesis (Consensus)

Recessive Scores

• pRec: 0.333

Intolerance Scores

• loftool: 0.564
• rvis_EVS: -0.65
• rvis_percentile_EVS: 16.36

Haploinsufficiency Scores

• pHI: 0.149
• hipred: N
• hipred_score: 0.401
• ghis: 0.615

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.756

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Zmpste24
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; muscle phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); 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; skeleton phenotype; renal/urinary system phenotype; immune system phenotype; limbs/digits/tail phenotype; digestive/alimentary 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); 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: liver development;hair follicle development;heart morphogenesis;ventricular cardiac muscle tissue development;cardiac ventricle development;growth plate cartilage development;DNA repair;proteolysis;inflammatory cell apoptotic process;nuclear envelope organization;adult walking behavior;determination of adult lifespan;regulation of cell shape;regulation of autophagy;regulation of glucose metabolic process;regulation of lipid metabolic process;bone mineralization;prenylated protein catabolic process;regulation of bone mineralization;regulation of TOR signaling;regulation of hormone metabolic process;multicellular organism growth;regulation of multicellular organism growth;maintenance of rDNA;regulation of DNA damage response, signal transduction by p53 class mediator;histone H2B-K5 acetylation;hypomethylation of CpG island;cellular lipid metabolic process;regulation of fibroblast proliferation;thymus development;cardiac muscle fiber development;regulation of defense response to virus;neuromuscular process;regulation of ventricular cardiac muscle cell membrane repolarization;kidney morphogenesis;cardiac conduction;CAMKK-AMPK signaling cascade;regulation of stress-activated protein kinase signaling cascade;cellular response to gamma radiation;CAAX-box protein processing;response to DNA damage checkpoint signaling;regulation of RNA polymerase II regulatory region sequence-specific DNA binding;regulation of mitotic cell cycle DNA replication;negative regulation of production of miRNAs involved in gene silencing by miRNA;calcium ion import into sarcoplasmic reticulum;histone H2A phosphorylation;regulation of histone H4-K16 acetylation;regulation of termination of RNA polymerase I transcription;regulation of cellular senescence
• Cellular component: nuclear inner membrane;membrane;integral component of endoplasmic reticulum membrane;protein-containing complex;extracellular exosome
• Molecular function: double-stranded DNA binding;metalloendopeptidase activity;protein binding;metalloexopeptidase activity;metal ion binding