VMA21
protein-codingvacuolar ATPase assembly factor VMA21
Gene summary
This gene encodes a chaperone for assembly of lysosomal vacuolar ATPase.[provided by RefSeq, Jul 2012]
- MEAX
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0015286
Submitter: ClinGen
VMA21 was first reported in relation to a congenital disorder of glycosylation in 2020 (PMID: 32145091). This gene is an assembly chaperone of the vacuolar ATPase mapped to chromosome X28 (PMID: 32145091). In addition to CDG, VMA21 has been associated with X-linked myopathy with excessive autophagy (XMEA) and follicular lymphoma (PMIDs: 37756622, 40033998) To date, three male patients with VMA21 mutations have been diagnosed with CDG syndrome (PMIDs: 32145091, 37756622, 40033998). Their clinical features range from liver cholestasis and steatosis to mild hypercholesterolemia. These symptoms were associated with increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at early ages, followed by hypercholesterolemia in two of these patients (PMIDs: 32145091, 40033998). The hemizygous mutations identified are single nucleotide substitutions resulting in missense mutations and premature stop codons (PMID: 32145091). While no animal model currently exists for this CDG, there are animal models for XMEA (PMID: 40033998). This may provide a platform for future studies. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ClinGen Congenital Disorders of Glycosylation GCEP on July 6, 2026 (SOP Version 12).
Inheritance Pattern: XL
Disease ID:MONDO:0010684
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010684
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010684
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
Intervention: General
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to VMA21 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001017980.4. 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 | 1 | 23 | 4 | 28 | ||
| missense | 1 | 38 | 3 | 1 | 43 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 1 | 40 | 26 | 5 | 72 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001017980.1 | 3 | MANE Select | |
| Ensembl | ENSP00000333255.6 | 3 | MANE Select | |
| RefSeq | NP_001350739.1 | 3 | Standard | |
| Ensembl | ENSP00000359386.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of ATPase activity
- vacuolar proton-transporting V-type ATPase complex assembly
Cellular Component
- lysosome
- vacuole
- endoplasmic reticulum membrane
- ER to Golgi transport vesicle membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000330374
- Coding exons
- 3
- Length
- 12850
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.776 | 26 | 39.8 | 0.654 | 0.00000314 | 641 |
| Missense (PolyPhen) | 8 | 16.286 | 0.49122 | 272 | ||
| Synonymous | -1.26 | 23 | 16.5 | 1.39 | 0.00000128 | 207 |
| Loss of Function | 1.50 | 0 | 2.61 | 0.00 | 1.64e-7 | 53 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for the assembly of the V0 complex of the vacuolar ATPase (V-ATPase) in the endoplasmic reticulum. {ECO:0000255|HAMAP-Rule:MF_03058, ECO:0000269|PubMed:19379691}.;
- Disease
- DISEASE: Myopathy, X-linked, with excessive autophagy (MEAX) [MIM:310440]: A muscle disorder characterized by childhood early onset of a slowly progressive proximal limb muscle weakness (especially in legs) and elevation of serum creatine kinase, without evidence of cardiac, respiratory or central nervous system involvement. Histopathological analysis reveals diseased muscle fibers that are not necrotic, but show abnormal autophagic vacuolation as a manifestation of excessive autophagic activity in skeletal muscle cells. {ECO:0000269|PubMed:19379691, ECO:0000269|PubMed:23315026, ECO:0000269|PubMed:24488655, ECO:0000269|PubMed:25683699}. Note=The disease is caused by mutations affecting the gene represented in this entry. VMA21 deficiency results in an increase of lysosomal pH from 4.7 to 5.2, which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids, which upregulates the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge together, and vacuolate the cell. {ECO:0000269|PubMed:23315026}.;
Intolerance Scores
- RVIS EVS
- 0.17
- RVIS percentile EVS
- 65.33
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- N
- Indispensability score
- 0.307
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |