VPS54

protein-coding

VPS54 subunit of GARP complex, the group of Protein phosphatase 1 regulatory subunits|Golgi associated retrograde protein (GARP) complex

Gene summary

This gene encodes for a protein that in yeast forms part of a trimeric vacuolar-protein-sorting complex that is required for retrograde transport of proteins from prevacuoles to the late Golgi compartment. As in yeast, mammalian Vps54 proteins contain a coiled-coil region and dileucine motifs. Alternative splicing results in multiple transcript variants encoding different isoforms [provided by RefSeq, Jul 2008]

MANE transcript

NM_016516.3

Inheritance

—

ClinVar variants

U:126B:6

Top phenotype

Tooth agenesis

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr2:63,892,146-64,019,428

External References & Databases

Ensembl (ENSG00000143952)

Transcript & Mutation Effects

hg38 • Region Span ~127.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS54 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 114

not providedTotal: 8

Tooth agenesisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016516.3. 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			4 clinvar		1 clinvar	5
missense			118 clinvar	4 clinvar	1 clinvar	123
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	126	4	2	132

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016516.3	RefSeq	NP_057600.2	22	MANE Select
ENST00000272322.9	Ensembl	ENSP00000272322.4	22	MANE Select
NM_001005739.2	RefSeq	NP_001005739.1	22	Standard
ENST00000354504.7	Ensembl	ENSP00000346499.3	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Retrograde transport at the Trans-Golgi-Network
Intra-Golgi and retrograde Golgi-to-ER traffic

Biological Process

Golgi to vacuole transport
lysosomal transport
protein transport
regulation of growth
retrograde transport, endosome to Golgi

Molecular Function

protein binding
syntaxin binding

Cellular Component

GARP complex
nucleoplasm
Golgi apparatus
trans-Golgi network
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000272322
Coding exons: 22
Length: 126927
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125731
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.951	425	484	0.878	0.0000229	6419
Missense (PolyPhen)		78	153.68	0.50756		2062
Synonymous	-0.374	177	171	1.04	0.00000846	1804
Loss of Function	5.77	7	51.8	0.135	0.00000256	691

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000031	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.000092	rare
European (Non-Finnish)	0.000090	0.000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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:18367545). Within the GARP complex, required to tether the complex to the TGN. Not involved in endocytic recycling (PubMed:25799061). {ECO:0000269|PubMed:18367545, ECO:0000269|PubMed:25799061}.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.610
RVIS EVS: -0.91
RVIS percentile EVS: 10.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.105

Gene Damage Prediction

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