VPS33A

VPS33A core subunit of CORVET and HOPS complexes, the group of CORVET complex|HOPS complex

Basic information

Region (hg38): 12:122229563-122266494

Links

ENSG00000139719 ∙ NCBI:65082 ∙ OMIM:610034 ∙ HGNC:18179 ∙ Uniprot:Q96AX1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mucopolysaccharidosis-plus syndrome (Moderate), mode of inheritance: AR
• mucopolysaccharidosis-plus syndrome (Strong), mode of inheritance: AR
• mucopolysaccharidosis-plus syndrome (Limited), mode of inheritance: AR
• mucopolysaccharidosis-plus syndrome (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mucopolysaccharidosis-plus syndrome	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	Biochemical; Cardiovascular; Musculoskeletal; Neurologic	27547915; 28013294

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VPS33A gene.

• not provided (228 variants)
• Inborn genetic diseases (18 variants)
• Mucopolysaccharidosis-plus syndrome (7 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VPS33A 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				65	3	68
missense			87	3	3	93
nonsense			1			1
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			3	4		7
non coding				32	39	71
Total	0	0	90	100	45

Variants in VPS33A

This is a list of pathogenic ClinVar variants found in the VPS33A region.

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

Position	Type	Phenotype	Significance	ClinVar
12-122232061-GA-G			Benign (Aug 13, 2019)
12-122232254-G-T			Uncertain significance (Dec 15, 2021)
12-122232267-A-G			Likely benign (May 04, 2022)
12-122232271-T-C		not specified	Uncertain significance (Jun 21, 2023)
12-122232297-T-A			Uncertain significance (Nov 22, 2022)
12-122232308-C-T			Uncertain significance (Jun 21, 2021)
12-122232312-G-A			Likely benign (Aug 21, 2022)
12-122232318-T-C			Likely benign (Apr 20, 2023)
12-122232361-G-A			Uncertain significance (Aug 19, 2022)
12-122232372-G-A			Likely benign (Dec 19, 2023)
12-122232384-C-A			Likely benign (Jul 25, 2023)
12-122232387-A-G			Likely benign (Aug 04, 2023)
12-122232410-G-A			Uncertain significance (May 16, 2021)
12-122232420-C-T			Likely benign (Aug 28, 2018)
12-122232446-A-C			Likely benign (Aug 23, 2022)
12-122232578-AT-A			Benign (Sep 26, 2018)
12-122232650-G-C			Likely benign (Apr 20, 2019)
12-122232846-G-A			Likely benign (Apr 23, 2021)
12-122232847-G-A			Uncertain significance (May 06, 2022)
12-122232847-G-C			Uncertain significance (Aug 15, 2022)
12-122232855-G-A			Likely benign (Sep 07, 2022)
12-122232860-T-G		not specified	Uncertain significance (Oct 13, 2023)
12-122232876-G-C			Uncertain significance (Jul 25, 2022)
12-122232895-C-T			Uncertain significance (Jun 19, 2023)
12-122232917-G-A		Mucopolysaccharidosis-plus syndrome	Pathogenic (Nov 16, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VPS33A	protein_coding	protein_coding	ENST00000267199	13	36958

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.182	0.818	125728	0	19	125747	0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.64	263	349	0.754	0.0000201	3886
Missense in Polyphen		72	111	0.64865		1234
Synonymous	-0.626	153	143	1.07	0.00000868	1166
Loss of Function	4.01	8	32.8	0.244	0.00000185	375

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000279	0.000275
Ashkenazi Jewish	0.00	0.00
East Asian	0.000110	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000969	0.0000967
Middle Eastern	0.000110	0.000109
South Asian	0.0000330	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act as a core component of the putative HOPS and CORVET endosomal tethering complexes which are proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations (PubMed:23351085, PubMed:24554770, PubMed:25266290, PubMed:25783203). Required for fusion of endosomes and autophagosomes with lysosomes; the function is dependent on its association with VPS16 but not VIPAS39 (PubMed:25783203). The function in autophagosome-lysosome fusion implicates STX17 but not UVRAG (PubMed:24554770). {ECO:0000269|PubMed:24554770, ECO:0000269|PubMed:25783203, ECO:0000305|PubMed:23351085, ECO:0000305|PubMed:25266290, ECO:0000305|PubMed:25783203}.
• Disease: DISEASE: Mucopolysaccharidosis-plus syndrome (MPSPS) [MIM:617303]: A form of mucopolysaccharidosis, a group of diseases characterized by excessive accumulation and secretion of oligomucopoloysaccharides. MPSPS is a multisystemic disorder characterized by coarse facial features, dysostosis multiplex, hepatosplenomegaly, respiratory difficulties, mental retardation, developmental delay, pyramidal signs, severe chronic anemia, renal involvement and cardiac defects. Laboratory analyses show proteinuria with glomerular foamy cells, excess secretion of urinary glycosaminoglycans, and extremely high levels of plasma heparan sulphate. Disease onset is in infancy. Most patients die in the first years of life due to cardiorespiratory failure. MPSPS inheritance is autosomal recessive. {ECO:0000269|PubMed:27547915, ECO:0000269|PubMed:28013294}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ebola Virus Pathway on Host;Ebola Virus Pathway on Host (Consensus)

Recessive Scores

• pRec: 0.163

Intolerance Scores

• loftool: 0.565
• rvis_EVS: 0.04
• rvis_percentile_EVS: 57.31

Haploinsufficiency Scores

• pHI: 0.306
• hipred: N
• hipred_score: 0.332
• ghis: 0.537

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.987

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vps33a
• Phenotype: hematopoietic system phenotype; pigmentation phenotype; renal/urinary system phenotype; vision/eye 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); homeostasis/metabolism phenotype

Gene ontology

• Biological process: vesicle docking involved in exocytosis;endosome to lysosome transport;protein transport;vesicle-mediated transport;platelet formation;melanosome localization;lysosome localization;regulation of lysosomal lumen pH;regulation of developmental pigmentation;autophagosome maturation
• Cellular component: lysosomal membrane;early endosome;late endosome;autophagosome;AP-3 adaptor complex;clathrin-coated vesicle;HOPS complex;late endosome membrane;perinuclear region of cytoplasm;clathrin complex
• Molecular function: protein binding