PIKFYVE

protein-coding

phosphoinositide kinase, FYVE-type zinc finger containing, the group of Zinc fingers FYVE-type

Gene summary

Phosphorylated derivatives of phosphatidylinositol (PtdIns) regulate cytoskeletal functions, membrane trafficking, and receptor signaling by recruiting protein complexes to cell- and endosomal-membranes. Humans have multiple PtdIns proteins that differ by the degree and position of phosphorylation of the inositol ring. This gene encodes an enzyme (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) that phosphorylates the D-5 position in PtdIns and phosphatidylinositol-3-phosphate (PtdIns3P) to make PtdIns5P and PtdIns(3,5)biphosphate. The D-5 position also can be phosphorylated by type I PtdIns4P-5-kinases (PIP5Ks) that are encoded by distinct genes and preferentially phosphorylate D-4 phosphorylated PtdIns. In contrast, PIKfyve preferentially phosphorylates D-3 phosphorylated PtdIns. In addition to being a lipid kinase, PIKfyve also has protein kinase activity. PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes. The protein plays a key role in cell entry of ebola virus and SARS-CoV-2 by endocytosis Mutations in this gene cause corneal fleck dystrophy (CFD); an autosomal dominant disorder characterized by numerous small white flecks present in all layers of the corneal stroma. Histologically, these flecks appear to be keratocytes distended with lipid and mucopolysaccharide filled intracytoplasmic vacuoles. [provided by RefSeq, Jul 2021]

Previous symbols:

PIP5K3

MANE transcript

NM_015040.4

Inheritance

ClinVar variants

P:38U:277B:89

Top phenotype

Corneal fleck dystrophy

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr2:208,266,255-208,358,746

External References & Databases

Ensembl (ENSG00000115020)

Transcript & Mutation Effects

hg38 • Region Span ~92.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fleck corneal dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007376

Submitter: Orphanet

fleck corneal dystrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007376

Submitter: PanelApp Australia

fleck corneal dystrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007376

Submitter: Labcorp Genetics (formerly Invitae)

fleck corneal dystrophyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007376

Submitter: G2P

Clinical Genomic Database (CGD)

Corneal fleck dystrophyAD

Manifestation: Ophthalmologic

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: 15902656; 23288988; 26396486

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIKFYVE variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 212

not providedTotal: 120

Fleck corneal dystrophyTotal: 101

PIKFYVE-related disorderTotal: 34

not specifiedTotal: 22

Corneal dystrophyTotal: 1

Familial hypercholesterolemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015040.4. 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			12 clinvar	38 clinvar	17 clinvar	67
missense	1 clinvar		254 clinvar	25 clinvar	9 clinvar	289
nonsense	4 clinvar	13 clinvar	2 clinvar			19
start loss						0
frameshift	5 clinvar	10 clinvar				15
splice donor/acceptor (+/-2bp)		5 clinvar	9 clinvar			14
Total	10	28	277	63	26	404

Highest pathogenic variant AF is 0.0000068153654

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015040.4	RefSeq	NP_055855.2	41	MANE Select
ENST00000264380.9	Ensembl	ENSP00000264380.4	41	MANE Select
NM_001178000.2	RefSeq	NP_001171471.1	11	Standard
NM_152671.4	RefSeq	NP_689884.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inositol phosphate metabolism - Homo sapiens (human)
Phagosome - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
Phosphatidylinositol signaling system - Homo sapiens (human)
Phosphatidylinositol Phosphate Metabolism

Biological Process

phosphatidylinositol biosynthetic process
receptor-mediated endocytosis
myelin assembly
protein localization to nucleus
intracellular signal transduction

Molecular Function

1-phosphatidylinositol-3-phosphate 5-kinase activity
protein binding
ATP binding
zinc ion binding
1-phosphatidylinositol-4-phosphate 5-kinase activity

Cellular Component

Golgi membrane
cytosol
cell-cell junction
endosome membrane
vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264380
Coding exons: 41
Length: 92485
Individuals with no LoFs: 125660
Homozygous LoFs: 0
Heterozygous LoFs: 88
Defined: 125748
p: 0.000350

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.05	928	1.12e+3	0.828	0.0000598	13870
Missense (PolyPhen)		289	436.58	0.66196		5297
Synonymous	0.118	392	395	0.992	0.0000209	3949
Loss of Function	7.15	35	119	0.294	0.00000711	1347

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00049	0.00049	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00036	0.00036	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	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). Catalyzes the phosphorylation of phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo- inositol ring, to form phosphatidylinositol 3,5-bisphosphate. Required for endocytic-vacuolar pathway and nuclear migration. Plays a role in the biogenesis of endosome carrier vesicles (ECV)/ multivesicular bodies (MVB) transport intermediates from early endosomes. {ECO:0000269|PubMed:17556371}.;
Disease: DISEASE: Corneal dystrophy, fleck (CFD) [MIM:121850]: A form of stromal corneal dystrophy characterized by numerous small white flecks scattered in all levels of the stroma, with configurations varying from semicircular to wreath-like, curvilinear, or punctate. Although CFD may occasionally cause mild photophobia, patients are typically asymptomatic and have normal vision. {ECO:0000269|PubMed:15902656}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.432

Intolerance Scores

LoFtool: 0.350
RVIS EVS: -1.4
RVIS percentile EVS: 4.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.986

Gene Damage Prediction

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