VPS53

VPS53 subunit of GARP complex, the group of Golgi associated retrograde protein (GARP) complex|Endosome-associated recycling protein (EARP) complex

Basic information

Region (hg38): 17:508502-721717

Links

ENSG00000141252 ∙ NCBI:55275 ∙ OMIM:615850 ∙ HGNC:25608 ∙ Uniprot:Q5VIR6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pontocerebellar hypoplasia type 2E (Strong), mode of inheritance: AR
• progressive cerebello-cerebral atrophy (Supportive), mode of inheritance: AR
• pontocerebellar hypoplasia, type 13 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pontocerebellar hypoplasia, type 2E	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	Neurologic	24577744

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VPS53 gene.

• not provided (232 variants)
• Inborn genetic diseases (33 variants)
• not specified (31 variants)
• Pontocerebellar hypoplasia type 2E (28 variants)
• Pontoneocerebellar hypoplasia (6 variants)
• Neurodevelopmental abnormality (1 variants)
• Microcephaly (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VPS53 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			1	54	7	62
missense	1		52	4	3	60
nonsense		2	2			4
start loss			1			1
frameshift		2				2
inframe indel						0
splice donor/acceptor (+/-2bp)		4				4
splice region		1	3	14	3	21
non coding				68	68	136
Total	1	8	56	126	78

Highest pathogenic variant AF is 0.0000394

Variants in VPS53

This is a list of pathogenic ClinVar variants found in the VPS53 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-519126-T-C		VPS53-related disorder	Likely benign (May 26, 2021)
17-519137-C-T			Likely benign (Dec 12, 2023)
17-519146-G-A			Likely benign (Dec 12, 2023)
17-519155-G-A		VPS53-related disorder	Likely benign (Jan 31, 2024)
17-519167-G-A			Likely benign (May 19, 2023)
17-519169-G-C		not specified	Conflicting classifications of pathogenicity (Jan 04, 2024)
17-519173-C-T			Likely benign (Jan 25, 2024)
17-519179-T-C			Likely benign (Sep 08, 2023)
17-519188-T-C			Likely benign (Sep 29, 2023)
17-519194-C-T			Likely benign (Mar 22, 2023)
17-519197-C-T			Likely benign (Dec 26, 2023)
17-519198-G-A		Inborn genetic diseases	Likely benign (Jun 16, 2022)
17-519200-C-G			Likely benign (Sep 08, 2023)
17-519207-A-G		Pontocerebellar hypoplasia type 2E	Uncertain significance (Jan 24, 2020)
17-519212-G-A			Likely benign (Jan 31, 2024)
17-519215-G-A			Likely benign (Jan 24, 2024)
17-519221-T-C			Likely benign (Jan 04, 2018)
17-519224-T-C			Likely benign (Oct 29, 2023)
17-519230-C-G			Likely benign (Jan 31, 2023)
17-519230-C-T			Benign/Likely benign (Jan 25, 2024)
17-519231-G-A		VPS53-related disorder	Likely benign (Jan 19, 2024)
17-519236-C-A			Likely benign (Jan 08, 2024)
17-519236-C-T			Likely benign (Jun 14, 2023)
17-519239-T-C			Likely benign (Dec 01, 2023)
17-519242-G-A			Likely benign (Oct 18, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VPS53	protein_coding	protein_coding	ENST00000437048	22	213050

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.40e-7	1.00	125689	0	59	125748	0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.58	374	470	0.795	0.0000272	5463
Missense in Polyphen		80	135.83	0.58899		1707
Synonymous	-0.284	190	185	1.03	0.0000117	1591
Loss of Function	3.70	20	47.5	0.421	0.00000262	532

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000420	0.000420
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000381	0.000381
Finnish	0.000647	0.000647
European (Non-Finnish)	0.000176	0.000176
Middle Eastern	0.000381	0.000381
South Asian	0.000197	0.000196
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN). The GARP complex is required for the maintenance of the cycling of mannose 6-phosphate receptors between the TGN and endosomes, this cycling is necessary for proper lysosomal sorting of acid hydrolases such as CTSD (PubMed:15878329, PubMed:18367545). Acts as component of the EARP complex that is involved in endocytic recycling. The EARP complex associates with Rab4-positive endosomes and promotes recycling of internalized transferrin receptor (TFRC) to the plasma membrane (PubMed:25799061). {ECO:0000269|PubMed:15878329, ECO:0000269|PubMed:18367545, ECO:0000269|PubMed:25799061}.
• Disease: DISEASE: Pontocerebellar hypoplasia 2E (PCH2E) [MIM:615851]: A neurodegenerative disorder characterized by progressive cerebello- cerebral atrophy, profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsy. {ECO:0000269|PubMed:24577744}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Vesicle-mediated transport;Membrane Trafficking;Retrograde transport at the Trans-Golgi-Network;Intra-Golgi and retrograde Golgi-to-ER traffic (Consensus)

Intolerance Scores

• loftool: 0.843
• rvis_EVS: -1.22
• rvis_percentile_EVS: 5.67

Haploinsufficiency Scores

• pHI: 0.305
• hipred: Y
• hipred_score: 0.554
• ghis: 0.604

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: N
• gene_indispensability_score: 0.348

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vps53
• Phenotype: growth/size/body region 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); embryo phenotype; skeleton phenotype

Gene ontology

• Biological process: lysosomal transport;protein transport;endocytic recycling;retrograde transport, endosome to Golgi
• Cellular component: GARP complex;Golgi apparatus;cytosol;endosome membrane;membrane;trans-Golgi network membrane;perinuclear region of cytoplasm;recycling endosome;EARP complex
• Molecular function: protein binding