VAC14

protein-coding

VAC14 component of PIKFYVE complex, the group of Armadillo like helical domain containing

Gene summary

This gene encodes a scaffold protein that is a component of the PIKfyve protein kinase complex. This complex is responsible for the synthesis of phosphatidylinositol 3,5-bisphosphate, an important component of cellular membranes, from phosphatidylinositol 3-phosphate. Mice lacking a functional copy of this gene exhibit severe neurodegeneration. Mutations in the human gene have been identified in patients with a childhood onset progressive neurological disorder characterized by impaired movement, dystonia, and striatal abnormalities. [provided by RefSeq, May 2017]

Previous symbols:

TAX1BP2

MANE transcript

NM_018052.5

Inheritance

ClinVar variants

P:18U:178B:165

Top phenotype

Striatonigral degeneration, childhood-onset

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr16:70,687,439-70,801,160

External References & Databases

Ensembl (ENSG00000103043)

Transcript & Mutation Effects

hg38 • Region Span ~113.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

striatonigral degeneration, childhood-onsetMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014889

Submitter: Ambry Genetics

hereditary neurological diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100545

Submitter: Ambry Genetics

striatonigral degeneration, childhood-onsetSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014889

Submitter: Labcorp Genetics (formerly Invitae)

Yunis-Varon syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008995

Submitter: Orphanet

striatonigral degeneration, childhood-onsetSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014889

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Striatonigral degeneration, childhood-onsetAR

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 27292112

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VAC14 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 407

Inborn genetic diseasesTotal: 105

Striatonigral degeneration, childhood-onsetTotal: 19

VAC14-related disorderTotal: 12

Yunis-Varon syndromeTotal: 2

NeurodegenerationTotal: 1

Myoepithelial tumorTotal: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018052.5. 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	147 clinvar	8 clinvar	156
missense	3 clinvar	3 clinvar	165 clinvar	7 clinvar	3 clinvar	181
nonsense	1 clinvar	1 clinvar	1 clinvar			3
start loss						0
frameshift	4 clinvar	1 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	10 clinvar			15
Total	10	8	178	154	11	361

Highest pathogenic variant AF is 0.000018587107

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018052.5	RefSeq	NP_060522.3	19	MANE Select
ENST00000261776.10	Ensembl	ENSP00000261776.5	19	MANE Select
NM_001351157.2	RefSeq	NP_001338086.1	14	Standard
ENST00000536184.6	Ensembl	ENSP00000439284.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HTLV-I infection - Homo sapiens (human)
Viral carcinogenesis - Homo sapiens (human)
Phosphatidylinositol Phosphate Metabolism
Joubert syndrome
Inositol Metabolism

Biological Process

phosphatidylinositol biosynthetic process
signal transduction
viral process

Molecular Function

protein binding
signaling receptor activity

Cellular Component

Golgi membrane
extrinsic component of vacuolar membrane
endoplasmic reticulum
endosome membrane
early endosome membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261776
Coding exons: 19
Length: 113723
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.17	335	467	0.717	0.0000278	5100
Missense (PolyPhen)		108	176.51	0.61185		1927
Synonymous	-0.974	228	210	1.09	0.0000134	1574
Loss of Function	4.29	9	37.3	0.241	0.00000167	444

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000061	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00020	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Acts as a positive activator of PIKfyve kinase activity. Also required to maintain normal levels of phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 5-phosphate (PtdIns(5)P). Plays a role in the biogenesis of endosome carrier vesicles (ECV) / multivesicular bodies (MVB) transport intermediates from early endosomes. {ECO:0000269|PubMed:15542851, ECO:0000269|PubMed:17556371}.;
Disease: DISEASE: Striatonigral degeneration, childhood-onset (SNDC) [MIM:617054]: An autosomal recessive neurological disorder characterized by sudden childhood onset of developmental regression. Affected children develop impaired movements with dystonia, progressively become non-ambulatory and non-verbal, and exhibit striatal abnormalities on MRI. {ECO:0000269|PubMed:27292112}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.223
RVIS EVS: -1.15
RVIS percentile EVS: 6.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.799

Gene Damage Prediction

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