VPS25

protein-coding

vacuolar protein sorting 25 homolog, the group of ESCRT-II

Gene summary

This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A pseudogene of this gene is present on chromosome 1. [provided by RefSeq, Jul 2013]

MANE transcript

NM_032353.4

Inheritance

—

ClinVar variants

P:2U:17B:1

Top phenotype

VPS25-related neurodevelopmental delay

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr17:42,773,449-42,779,599

External References & Databases

Ensembl (ENSG00000131475)

Transcript & Mutation Effects

hg38 • Region Span ~6.2 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 VPS25 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 15

VPS25-related neurodevelopmental delayTotal: 3

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032353.4. 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			1 clinvar			1
missense		2 clinvar	15 clinvar		1 clinvar	18
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	2	17	0	1	20

Highest pathogenic variant AF is 0.000016727132

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032353.4	RefSeq	NP_115729.1	6	MANE Select
ENST00000253794.7	Ensembl	ENSP00000253794.1	6	MANE Select
ENST00000589520.1	Ensembl	ENSP00000465798.1	4	Standard
ENST00000589577.1	Ensembl	ENSP00000467225.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Vesicle-mediated transport
Membrane Trafficking
Endosomal Sorting Complex Required For Transport (ESCRT)

Biological Process

negative regulation of epidermal growth factor-activated receptor activity
endosomal transport
macroautophagy
multivesicular body assembly
protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

Molecular Function

structural molecule activity
protein binding
protein homodimerization activity
protein N-terminus binding

Cellular Component

ESCRT II complex
nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000253794
Coding exons: 6
Length: 6164
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	59	101	0.585	0.00000530	1159
Missense (PolyPhen)		15	37.049	0.40487		417
Synonymous	-0.516	47	42.7	1.10	0.00000248	314
Loss of Function	2.24	4	12.6	0.317	5.50e-7	126

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the ESCRT-II complex (endosomal sorting complex required for transport II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs. The MVB pathway mediates delivery of transmembrane proteins into the lumen of the lysosome for degradation. The ESCRT-II complex is probably involved in the recruitment of the ESCRT-III complex. The ESCRT-II complex may also play a role in transcription regulation, possibly via its interaction with ELL. The ESCRT-II complex may be involved in facilitating the budding of certain RNA viruses. {ECO:0000269|PubMed:18723511}.;

Recessive Scores

pRec: 0.136

Intolerance Scores

LoFtool: 0.398
RVIS EVS: 0.08
RVIS percentile EVS: 59.76

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.958

Gene Damage Prediction

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