VPS4A

protein-coding

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

Gene summary

The protein encoded by this gene is a member of the AAA protein family (ATPases associated with diverse cellular activities), and is the homolog of the yeast Vps4 protein. In humans, two paralogs of the yeast protein have been identified. The former share a high degree of aa sequence similarity with each other, and also with yeast Vps4 and mouse Skd1 proteins. The mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be really an yeast Vps4 ortholog. Functional studies indicate that both human paralogs associate with the endosomal compartments, and are involved in intracellular protein trafficking, similar to Vps4 protein in yeast. The gene encoding this paralog has been mapped to chromosome 16; the gene for the other resides on chromosome 18. [provided by RefSeq, Jul 2008]

MANE transcript

NM_013245.3

Inheritance

AD, AR

ClinVar variants

P:7U:76B:16

Top phenotype

CIMDAG syndrome

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr16:69,311,336-69,326,939

External References & Databases

Ensembl (ENSG00000132612)

Transcript & Mutation Effects

hg38 • Region Span ~15.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disabilityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0035819

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0035819

Submitter: G2P

cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0035819

Submitter: G2P

cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0035819

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

CIMDAG syndromeAD

Manifestation: Craniofacial; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Hematologic

Rationale: Among other findings, individuals have been described as having transfusion-dependent anemia, and awareness may allow early diagnosis and medical management

Refs: 33186543; 33186545; 33460484

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS4A variants in ClinVar

7 Conditions Cataloged

not providedTotal: 41

Inborn genetic diseasesTotal: 41

Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndromeTotal: 16

VPS4A-related disorderTotal: 5

Syndromic congenital hemolytic and dyserythropoietic anemiaTotal: 3

not specifiedTotal: 2

Generalized dystoniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013245.3. 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			2 clinvar	7 clinvar	3 clinvar	12
missense	4 clinvar	3 clinvar	65 clinvar	6 clinvar		78
nonsense			3 clinvar			3
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	4	3	76	13	3	99

Highest pathogenic variant AF is 0.0000013685489

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013245.3	RefSeq	NP_037377.1	11	MANE Select
ENST00000254950.13	Ensembl	ENSP00000254950.11	11	MANE Select
ENST00000714472.1	Ensembl	ENSP00000519729.1	3	Standard
ENST00000714473.1	Ensembl	ENSP00000519730.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Necroptosis - Homo sapiens (human)
Ebola Virus Pathway on Host
Ebola Virus Pathway on Host
Disease

Biological Process

actomyosin contractile ring contraction
protein targeting to lysosome
vesicle budding from membrane
nucleus organization
nuclear envelope organization

Molecular Function

protein binding
ATP binding
protein C-terminus binding
ATPase activity
protein domain specific binding

Cellular Component

spindle pole
nucleus
cytoplasm
lysosome
endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000254950
Coding exons: 11
Length: 13691
Individuals with no LoFs: 124630
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 124637
p: 0.0000281

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.69	147	272	0.541	0.0000168	2851
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.224

Intolerance Scores

LoFtool: 0.197
RVIS EVS: -0.85
RVIS percentile EVS: 11.06

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.842

Gene Damage Prediction

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