VMA21

vacuolar ATPase assembly factor VMA21

Basic information

Region (hg38): X:151396515-151409364

Previous symbols: [ "MEAX" ]

Links

ENSG00000160131 ∙ NCBI:203547 ∙ OMIM:300913 ∙ HGNC:22082 ∙ Uniprot:Q3ZAQ7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked myopathy with excessive autophagy (Supportive), mode of inheritance: XL
• X-linked myopathy with excessive autophagy (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myopathy, X-linked, with excessive autophagy	XL	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	Musculoskeletal	23315026; 23850239; 25683699; 25809233; 25817839

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VMA21 gene.

• X-linked_myopathy_with_excessive_autophagy (77 variants)
• Inborn_genetic_diseases (13 variants)
• VMA21-related_disorder (5 variants)
• not_provided (4 variants)
• not_specified (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VMA21 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001017980.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				17	6	23
missense		1	32	3	1	37
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	1	32	20	7

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VMA21	protein_coding	protein_coding	ENST00000330374	3	12850

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.572	0.386	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.776	26	39.8	0.654	0.00000314	641
Missense in 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

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: 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

Haploinsufficiency Scores

• hipred: N
• hipred_score: 0.462
• ghis: 0.536

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: N
• gene_indispensability_score: 0.307

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vma21

Gene ontology

• 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;endoplasmic reticulum-Golgi intermediate compartment membrane