VPS4A

vacuolar protein sorting 4 homolog A, the group of ESCRT-IV|AAA ATPases

Basic information

Region (hg38): 16:69311336-69326939

Links

ENSG00000132612 ∙ NCBI:27183 ∙ OMIM:609982 ∙ HGNC:13488 ∙ Uniprot:Q9UN37 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability (Limited), mode of inheritance: AD
• cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
CIMDAG syndrome	AD	Hematologic	Among other findings, individuals have been described as having transfusion-dependent anemia, and awareness may allow early diagnosis and medical management	Craniofacial; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic	33186543; 33186545; 33460484

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VPS4A gene.

• Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome (4 variants)
• not provided (3 variants)
• Syndromic congenital hemolytic and dyserythropoietic anemia (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VPS4A 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			1	3	3	7
missense	4	1	24	6		35
nonsense			2			2
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			1	1		2
non coding					1	1
Total	4	1	29	9	4

Variants in VPS4A

This is a list of pathogenic ClinVar variants found in the VPS4A region.

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

Position	Type	Phenotype	Significance	ClinVar
16-69316040-G-C		Inborn genetic diseases	Uncertain significance (Apr 19, 2024)
16-69316069-C-T		Syndromic congenital hemolytic and dyserythropoietic anemia • Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome	Likely pathogenic (Mar 13, 2023)
16-69316083-C-G		Inborn genetic diseases	Uncertain significance (Dec 03, 2021)
16-69316091-G-A			Benign (Jul 06, 2018)
16-69316108-A-G		Inborn genetic diseases	Uncertain significance (Feb 05, 2024)
16-69316119-T-C			Uncertain significance (Feb 01, 2022)
16-69316132-A-C			Benign (Dec 19, 2019)
16-69316236-A-G		Inborn genetic diseases	Uncertain significance (Sep 30, 2021)
16-69316272-G-A		Inborn genetic diseases	Likely benign (Dec 01, 2022)
16-69316353-A-G		Inborn genetic diseases	Likely benign (Jan 10, 2023)
16-69318649-G-A		Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome	Uncertain significance (Apr 04, 2024)
16-69318819-G-A		Inborn genetic diseases	Likely benign (Dec 19, 2021)
16-69318825-G-A			Likely pathogenic (Mar 21, 2024)
16-69318828-G-A		Inborn genetic diseases	Likely benign (Jul 25, 2023)
16-69318833-G-A		VPS4A-related disorder	Likely benign (Feb 20, 2024)
16-69318852-C-T		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
16-69318869-C-T			Likely benign (Mar 01, 2022)
16-69318878-G-A			Uncertain significance (Apr 01, 2024)
16-69318880-G-T		VPS4A-related disorder	Uncertain significance (May 06, 2023)
16-69318897-A-G			Uncertain significance (Oct 01, 2021)
16-69319398-C-T			Uncertain significance (Dec 16, 2022)
16-69319422-G-C			Uncertain significance (Mar 23, 2023)
16-69319521-A-G			Uncertain significance (May 01, 2019)
16-69319528-T-C		Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome	Uncertain significance (Aug 20, 2021)
16-69319531-G-A		Syndromic congenital hemolytic and dyserythropoietic anemia • Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome	Pathogenic (May 01, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VPS4A	protein_coding	protein_coding	ENST00000254950	11	13691

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.945	0.0553	124630	0	7	124637	0.0000281

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.69	147	272	0.541	0.0000168	2851
Missense in Polyphen		22	82.373	0.26708		835
Synonymous	-1.54	136	115	1.18	0.00000790	836
Loss of Function	3.79	3	22.4	0.134	0.00000120	257

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000871	0.0000871
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000469	0.0000464
European (Non-Finnish)	0.0000177	0.0000177
Middle Eastern	0.00	0.00
South Asian	0.0000328	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in late steps of the endosomal multivesicular bodies (MVB) pathway. Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly, possibly in combination with membrane fission. Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses). Involved in cytokinesis: retained at the midbody by ZFYVE19/ANCHR and CHMP4C until abscission checkpoint signaling is terminated at late cytokinesis. It is then released following dephosphorylation of CHMP4C, leading to abscission (PubMed:24814515). VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). {ECO:0000269|PubMed:11563910, ECO:0000269|PubMed:11595185, ECO:0000269|PubMed:15075231, ECO:0000269|PubMed:22660413, ECO:0000269|PubMed:24814515}.
• Pathway: Endocytosis - Homo sapiens (human);Necroptosis - Homo sapiens (human);Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Disease;Vesicle-mediated transport;Membrane Trafficking;Budding and maturation of HIV virion;Late Phase of HIV Life Cycle;HIV Life Cycle;HIV Infection;Endosomal Sorting Complex Required For Transport (ESCRT);Infectious disease;CXCR4-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.224

Intolerance Scores

• loftool: 0.197
• rvis_EVS: -0.85
• rvis_percentile_EVS: 11.06

Haploinsufficiency Scores

• pHI: 0.552
• hipred: Y
• hipred_score: 0.743
• ghis: 0.596

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.842

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vps4a
• Phenotype: immune system 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); hematopoietic system phenotype; embryo phenotype; homeostasis/metabolism phenotype; craniofacial 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

Gene ontology

• Biological process: actomyosin contractile ring contraction;protein targeting to lysosome;vesicle budding from membrane;nucleus organization;nuclear envelope organization;vacuole organization;mitotic metaphase plate congression;abscission;vesicle-mediated transport;endosomal transport;macroautophagy;viral life cycle;viral release from host cell;nuclear envelope reassembly;intracellular cholesterol transport;negative regulation of cytokinesis;regulation of protein localization;endosomal vesicle fusion;multivesicular body assembly;viral budding via host ESCRT complex;ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway;mitotic cytokinesis checkpoint;cell division;cytoskeleton-dependent cytokinesis;late endosomal microautophagy;midbody abscission;vesicle uncoating;ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway;positive regulation of viral release from host cell;regulation of protein localization to plasma membrane;positive regulation of exosomal secretion;positive regulation of viral budding via host ESCRT complex;positive regulation of viral life cycle;ESCRT complex disassembly;ESCRT III complex disassembly
• Cellular component: spindle pole;nucleus;cytoplasm;lysosome;endosome;early endosome;late endosome;vacuolar membrane;centrosome;cytosol;plasma membrane;endosome membrane;midbody;late endosome membrane;perinuclear region of cytoplasm;extracellular exosome;Flemming body
• Molecular function: protein binding;ATP binding;protein C-terminus binding;ATPase activity;protein domain specific binding;ATPase activity, coupled;protein-containing complex binding