VPS33B

VPS33B late endosome and lysosome associated

Basic information

Region (hg38): 15:90998672-91022603

Links

ENSG00000184056 ∙ NCBI:26276 ∙ OMIM:608552 ∙ HGNC:12712 ∙ Uniprot:Q9H267 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• arthrogryposis, renal dysfunction, and cholestasis 1 (Definitive), mode of inheritance: AR
• arthrogryposis-renal dysfunction-cholestasis syndrome (Supportive), mode of inheritance: AR
• arthrogryposis, renal dysfunction, and cholestasis 1 (Strong), mode of inheritance: AR
• arthrogryposis, renal dysfunction, and cholestasis 1 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Keratoderma-ichthyosis-deafness syndrome, autosomal recessive; Cholestasis, progressive familial intrahepatic, 12; Arthrogryposis, renal dysfunction, and cholestasis 1	AR	Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Renal	Individuals with Keratoderma-ichthyosis-deafness syndrome, autosomal recessive have been described with hearing impairment, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Cholestasis, progressive familial intrahepatic has been described as involving early-onset hepatic dysfunction, and medical and surgical interventions have been described as beneficial in some individuals; Individuals with Arthrogryposis, renal dysfunction, and cholestasis 1 may have manifstations including hearing loss, cardiovascular anomalies, renal dysfunction, and cholestasis, and awareness may allow early diagnosis and medical or surgical management of these sequelae	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal; Renal	28017832; 30561130; 31479177

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VPS33B gene.

• not provided (264 variants)
• Arthrogryposis, renal dysfunction, and cholestasis 1 (76 variants)
• Inborn genetic diseases (31 variants)
• not specified (25 variants)
• VPS33B-related condition (6 variants)
• Keratoderma-ichthyosis-deafness syndrome, autosomal recessive (2 variants)
• Cholestasis, progressive familial intrahepatic, 12 (1 variants)
• Abnormal bleeding;Thrombocytopenia (1 variants)
• Arthrogryposis with renal dysfunction and cholestasis syndrome (1 variants)
• Microcephaly (1 variants)
• - (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VPS33B 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			8	15	6	29
missense		1	103	2	1	107
nonsense	10	1				11
start loss						0
frameshift	5	1				6
inframe indel		1				1
splice donor/acceptor (+/-2bp)	4	3				7
splice region	1	2	9	8	1	21
non coding			15	52	59	126
Total	19	7	126	69	66

Highest pathogenic variant AF is 0.0000461

Variants in VPS33B

This is a list of pathogenic ClinVar variants found in the VPS33B region.

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

Position	Type	Phenotype	Significance	ClinVar
15-90998713-A-C		Arthrogryposis, renal dysfunction, and cholestasis 1	Uncertain significance (Jan 12, 2018)
15-90998714-A-T		Arthrogryposis, renal dysfunction, and cholestasis 1	Uncertain significance (Apr 27, 2017)
15-90998820-T-C		Arthrogryposis, renal dysfunction, and cholestasis 1	Uncertain significance (Jan 12, 2018)
15-90998850-G-A		Arthrogryposis, renal dysfunction, and cholestasis 1	Uncertain significance (Jan 12, 2018)
15-90998862-C-T		Arthrogryposis, renal dysfunction, and cholestasis 1	Uncertain significance (Jan 13, 2018)
15-90998965-G-A		Arthrogryposis, renal dysfunction, and cholestasis 1	Uncertain significance (Jan 12, 2018)
15-90998978-G-A			Uncertain significance (Aug 15, 2017)
15-90998988-TC-AG			Uncertain significance (Apr 07, 2022)
15-90999013-C-T		VPS33B-related disorder	Uncertain significance (Oct 04, 2023)
15-90999014-G-A			Likely benign (Jun 28, 2017)
15-90999015-C-T		Inborn genetic diseases	Uncertain significance (Jun 07, 2023)
15-90999023-G-T			Likely benign (Feb 28, 2018)
15-90999032-C-T			Likely benign (Jun 27, 2023)
15-90999033-G-A		Inborn genetic diseases	Uncertain significance (Aug 15, 2023)
15-90999047-C-T			Likely benign (Jul 17, 2023)
15-90999049-T-C		Arthrogryposis, renal dysfunction, and cholestasis 1 • not specified	Conflicting classifications of pathogenicity (Feb 14, 2023)
15-90999061-A-G			Likely benign (Jun 23, 2023)
15-90999068-T-C		Arthrogryposis, renal dysfunction, and cholestasis 1	Conflicting classifications of pathogenicity (Sep 01, 2023)
15-90999107-C-T			Benign (Nov 12, 2018)
15-90999183-G-GC			Likely benign (Jan 13, 2021)
15-90999188-GC-G			Likely benign (Jan 13, 2021)
15-90999251-GT-G			Benign (Nov 12, 2018)
15-90999286-A-G			Benign (Jul 31, 2019)
15-90999318-GT-G			Benign (Sep 04, 2019)
15-90999318-G-GT			Benign (Aug 20, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VPS33B	protein_coding	protein_coding	ENST00000333371	23	24188

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.41e-16	0.582	125653	0	95	125748	0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.364	314	333	0.944	0.0000205	4057
Missense in Polyphen		99	113.1	0.87533		1287
Synonymous	0.320	120	125	0.964	0.00000696	1149
Loss of Function	1.76	31	43.5	0.712	0.00000282	477

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000792	0.000792
Ashkenazi Jewish	0.000794	0.000794
East Asian	0.000489	0.000489
Finnish	0.00	0.00
European (Non-Finnish)	0.000387	0.000387
Middle Eastern	0.000489	0.000489
South Asian	0.000201	0.000196
Other	0.000652	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. Mediates phagolysosomal fusion in macrophages (PubMed:18474358). Proposed to be involved in endosomal maturation implicating VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical recycling pathway and in the maintenance of the apical-basolateral polarity (PubMed:20190753). Seems to be involved in the sorting of specific cargos from the trans-Golgi network to alpha-granule-destined multivesicular bodies (MVBs) promoting MVBs maturation in megakaryocytes (By similarity). {ECO:0000250|UniProtKB:P59016, ECO:0000269|PubMed:18474358, ECO:0000305|PubMed:20190753, ECO:0000305|PubMed:23918659}.
• Disease: DISEASE: Arthrogryposis, renal dysfunction and cholestasis syndrome 1 (ARCS1) [MIM:208085]: A multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity. Platelet dysfunction is common. {ECO:0000269|PubMed:15052268, ECO:0000269|PubMed:18853461, ECO:0000269|PubMed:20190753, ECO:0000269|PubMed:22753090, ECO:0000269|PubMed:23918659}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.118

Intolerance Scores

• loftool: 0.822
• rvis_EVS: -0.53
• rvis_percentile_EVS: 20.82

Haploinsufficiency Scores

• pHI: 0.0591
• hipred: Y
• hipred_score: 0.516
• ghis: 0.554

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.789

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vps33b
• 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); muscle phenotype; homeostasis/metabolism phenotype; skeleton 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; immune system phenotype

Zebrafish Information Network

• Gene name: vps33b
• Affected structure: enterocyte
• Phenotype tag: abnormal
• Phenotype quality: dilated

Gene ontology

• Biological process: vesicle docking involved in exocytosis;endosome organization;endosome to lysosome transport;protein transport;vesicle-mediated transport;peptidyl-lysine hydroxylation;melanosome localization;lysosome localization;collagen metabolic process;membrane fusion;platelet alpha granule organization;autophagosome maturation
• Cellular component: cytoplasm;lysosome;lysosomal membrane;late endosome;Golgi apparatus;AP-3 adaptor complex;clathrin-coated vesicle;HOPS complex;platelet alpha granule;early endosome membrane;late endosome membrane;perinuclear region of cytoplasm;recycling endosome;clathrin complex
• Molecular function: protein binding