VPS16

protein-coding

VPS16 core subunit of CORVET and HOPS complexes, the group of CORVET complex|HOPS complex

Gene summary

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps16 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

MANE transcript

NM_022575.4

Inheritance

AR, AD

ClinVar variants

P:26U:224B:23

Top phenotype

Dystonia 30

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr20:2,840,703-2,866,732

External References & Databases

Ensembl (ENSG00000215305)

Transcript & Mutation Effects

hg38 • Region Span ~26.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

isolated dystoniaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015494

Submitter: Ambry Genetics

dystonia 30LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0025691

Submitter: Labcorp Genetics (formerly Invitae)

dystonia 30STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0025691

Submitter: Labcorp Genetics (formerly Invitae)

mucopolysaccharidosis or mucopolysaccharidosis-like disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100365

Submitter: PanelApp Australia

dystonia 30STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0025691

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Dystonia 30AD/AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Response to deep brain stimulation has been described

Refs: 27174565; 32808683; 33482438

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VPS16 variants in ClinVar

12 Conditions Cataloged

Inborn genetic diseasesTotal: 165

not providedTotal: 74

Dystonia 30Total: 33

VPS16-related disorderTotal: 7

not specifiedTotal: 5

AutismTotal: 1

SplenomegalyTotal: 1

VPS16-associated disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022575.4. 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			4 clinvar	14 clinvar	3 clinvar	21
missense	2 clinvar		198 clinvar	5 clinvar	1 clinvar	206
nonsense	5 clinvar	6 clinvar	4 clinvar			15
start loss						0
frameshift	5 clinvar	4 clinvar	6 clinvar			15
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	12 clinvar			16
Total	13	13	224	19	4	273

Highest pathogenic variant AF is 0.00007434898

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022575.4	RefSeq	NP_072097.2	24	MANE Select
ENST00000380445.8	Ensembl	ENSP00000369810.3	24	MANE Select
NM_080413.3	RefSeq	NP_536338.1	20	Standard
ENST00000380469.7	Ensembl	ENSP00000369836.3	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ebola Virus Pathway on Host
Ebola Virus Pathway on Host

Biological Process

intracellular protein transport
vacuole organization
endosome to lysosome transport
endosomal transport
regulation of vacuole fusion, non-autophagic

Molecular Function

actin binding
protein binding
actin filament binding

Cellular Component

lysosome
lysosomal membrane
endosome
early endosome
late endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380445
Coding exons: 24
Length: 26030
Individuals with no LoFs: 125697
Homozygous LoFs: 0
Heterozygous LoFs: 51
Defined: 125748
p: 0.000203

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.823	458	510	0.897	0.0000321	5454
Missense (PolyPhen)		158	193.89	0.81488		1979
Synonymous	0.861	184	199	0.922	0.0000120	1654
Loss of Function	2.62	32	52.5	0.609	0.00000298	555

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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:11382755, PubMed:23351085, PubMed:24554770, PubMed:25266290, PubMed:25783203). Required for recruitment of VPS33A to the HOPS complex (PubMed:23901104). Required for fusion of endosomes and autophagosomes with lysosomes; the function is dependent on its association with VPS33A but not VPS33B (PubMed:25783203). The function in autophagosome-lysosome fusion implicates STX17 but not UVRAG (PubMed:24554770). {ECO:0000269|PubMed:23901104, ECO:0000269|PubMed:24554770, ECO:0000269|PubMed:25783203, ECO:0000305|PubMed:11382755, ECO:0000305|PubMed:23351085, ECO:0000305|PubMed:25266290, ECO:0000305|PubMed:25783203}.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.817
RVIS EVS: -0.9
RVIS percentile EVS: 10.14

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.890

Gene Damage Prediction

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