ZFYVE26

protein-coding

zinc finger FYVE-type containing 26, the group of Zinc fingers FYVE-type

Gene summary

This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

Previous symbols:

SPG15

MANE transcript

NM_015346.4

Inheritance

ClinVar variants

P:422U:812B:1058

Top phenotype

Spastic paraplegia 15, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr14:67,727,374-67,816,590

External References & Databases

Ensembl (ENSG00000072121)

Transcript & Mutation Effects

hg38 • Region Span ~89.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 15SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010044

Submitter: Orphanet

hereditary spastic paraplegia 15DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010044

Submitter: G2P

hereditary spastic paraplegia 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010044

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010044

Submitter: PanelApp Australia

hereditary spastic paraplegia 15DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010044

Submitter: Myriad Women's Health

Clinical Genomic Database (CGD)

Spastic paraplegia 15, autosomal recessiveAR

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: 11342696; 14745065; 17661097; 19438933; 18394578; 19805727

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZFYVE26 variants in ClinVar

14 Conditions Cataloged

Spastic paraplegiaTotal: 2258

not providedTotal: 466

Hereditary spastic paraplegia 15Total: 420

Inborn genetic diseasesTotal: 367

Hereditary spastic paraplegiaTotal: 110

not specifiedTotal: 86

ZFYVE26-related disorderTotal: 31

Tip-toe gaitTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015346.4. 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		2 clinvar	15 clinvar	990 clinvar	14 clinvar	1021
missense	2 clinvar	14 clinvar	784 clinvar	46 clinvar	8 clinvar	854
nonsense	82 clinvar	62 clinvar	4 clinvar			148
start loss	1 clinvar					1
frameshift	91 clinvar	91 clinvar	2 clinvar			184
splice donor/acceptor (+/-2bp)	7 clinvar	70 clinvar	7 clinvar			84
Total	183	239	812	1036	22	2292

Highest pathogenic variant AF is 0.00008735962

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015346.4	RefSeq	NP_056161.2	41	MANE Select
ENST00000347230.9	Ensembl	ENSP00000251119.5	41	MANE Select
ENST00000554557.5	Ensembl	ENSP00000450431.1	8	Standard
ENST00000555452.1	Ensembl	ENSP00000450603.1	34	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
zfyve26	Danio rerio	Structure: motor neuron Quality: branchiness abnormal

Gene / Model

Organism

Observed Phenotype

zfyve26

Danio rerio

Structure: motor neuron

Quality: branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitotic cytokinesis
double-strand break repair via homologous recombination
regulation of cytokinesis

Molecular Function

protein binding
phosphatidylinositol-3-phosphate binding
metal ion binding

Cellular Component

lysosomal membrane
centrosome
midbody

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000347230
Coding exons: 41
Length: 89217
Individuals with no LoFs: 125614
Homozygous LoFs: 0
Heterozygous LoFs: 134
Defined: 125748
p: 0.000533

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.520	1280	1.33e+3	0.960	0.0000775	16499
Missense (PolyPhen)		314	382.62	0.82065		5122
Synonymous	0.511	521	536	0.972	0.0000301	5150
Loss of Function	5.23	58	120	0.484	0.00000624	1427

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00043	0.00044	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00069	0.00069	rare
South Asian	0.00059	0.00059	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Phosphatidylinositol 3-phosphate-binding protein required for the abcission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abcission. May also be required for efficient homologous recombination DNA double-strand break repair. {ECO:0000269|PubMed:20208530}.;
Disease: DISEASE: Spastic paraplegia 15, autosomal recessive (SPG15) [MIM:270700]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG15 is a complex form associated with additional neurological symptoms such as cognitive deterioration or mental retardation, axonal neuropathy, mild cerebellar signs, and, less frequently, a central hearing deficit, decreased visual acuity, or retinal degeneration. {ECO:0000269|PubMed:18394578, ECO:0000269|PubMed:19084844, ECO:0000269|PubMed:19805727}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.892
RVIS EVS: -0.27
RVIS percentile EVS: 33.59

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.397

Gene Damage Prediction

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