ZFYVE27

protein-coding

zinc finger FYVE-type containing 27, the group of Zinc fingers FYVE-type

Gene summary

This gene encodes a protein with several transmembrane domains, a Rab11-binding domain and a lipid-binding FYVE finger domain. The encoded protein appears to promote neurite formation. A mutation in this gene has been reported to be associated with hereditary spastic paraplegia, however the pathogenicity of the mutation, which may simply represent a polymorphism, is unclear. [provided by RefSeq, Mar 2010]

MANE transcript

NM_001385875.1

Inheritance

ClinVar variants

U:119B:46

Top phenotype

Spastic paraplegia 33, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr10:97,737,121-97,760,907

External References & Databases

Ensembl (ENSG00000155256)

Transcript & Mutation Effects

hg38 • Region Span ~23.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 33LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012448

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 33NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0012448

Submitter: ClinGen

ZFYVE27 was first reported in relation to autosomal dominant hereditary spastic paraplegia (HSP) in 2006 (Mannan et al., PMID: 16826525). In this study, a missense variant (c.572G>T; p.G191V) was identified in three related individuals with HSP, following targeted sequencing of the ZFYVE27 gene. No whole exome or genome approaches were used, and the authors did not state whether any other HSP genes had been previously tested. The population allele frequencies for the p.G191V variant identified in this family are higher than would be expected for disease-causing variants, and therefore was not scored. A second family was reported in 2015 (PMID: 25497598) with a splice acceptor variant [c.8052-2A-G]. This variant was also reported in the general population and was not scored. The assertion that the variant in ZFYVE27 was causative was attributed to the original Mannan et al., study. Experimental cell models have demonstrated that ZFYVE27 was found to localize predominantly to the tubular endoplasmic reticulum (ER) and forced expression of protrudin promoted the formation and stabilization of the tubular ER network (PMID: 24668814). However, there was conflicting evidence whether the G191V variant impaired the function of ZFYVE27 protein (PMIDs: 18606302 and 24668814). In summary, the evidence supporting the relationship between ZFYVE27 and autosomal dominant hereditary spastic paraplegia has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role ZFYVE27 plays in this disease. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on February 2, 2023 (SOP Version 9).

hereditary spastic paraplegia 33LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012448

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spastic paraplegia 33, autosomal dominantAD

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: 16826525; 18606302

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZFYVE27 variants in ClinVar

6 Conditions Cataloged

Spastic paraplegiaTotal: 110

not specifiedTotal: 80

Hereditary spastic paraplegia 33Total: 30

not providedTotal: 20

ZFYVE27-related disorderTotal: 3

Spastic tetraparesisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001385875.1. 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	33 clinvar	1 clinvar	36
missense			99 clinvar	9 clinvar	3 clinvar	111
nonsense			2 clinvar			2
start loss			1 clinvar			1
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			11 clinvar			11
Total	0	0	119	42	4	165

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 142 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001385875.1	RefSeq	NP_001372804.1	12	MANE Select
ENST00000684270.1	Ensembl	ENSP00000506975.1	12	MANE Select
NM_001002261.4	RefSeq	NP_001002261.1	12	Standard
NM_001002262.4	RefSeq	NP_001002262.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
zfyve27	Danio rerio	Structure: primary motor neuron Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

zfyve27

Danio rerio

Structure: primary motor neuron

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)

Biological Process

vesicle-mediated transport
neuron projection development
positive regulation of axon extension
neurotrophin TRK receptor signaling pathway
endoplasmic reticulum tubular network formation

Molecular Function

protein binding
protein self-association
metal ion binding

Cellular Component

nucleoplasm
endoplasmic reticulum
cytosol
integral component of membrane
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356257
Coding exons: 12
Length: 23787
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.818	210	246	0.853	0.0000156	2685
Missense (PolyPhen)		73	78.583	0.92896		741
Synonymous	-0.288	109	105	1.04	0.00000695	835
Loss of Function	1.16	17	23.0	0.739	0.00000123	269

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00043	0.00044	rare
Finnish	0.00051	0.00051	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key regulator of RAB11-dependent vesicular trafficking during neurite extension through polarized membrane transport (PubMed:17082457). Promotes axonal elongation and contributes to the establishment of neuronal cell polarity (By similarity). Involved in nerve growth factor-induced neurite formation in VAPA- dependent manner (PubMed:19289470). Contributes to both the formation and stabilization of the tubular ER network (PubMed:24668814). Involved in ER morphogenesis by regulating the sheet-to-tubule balance and possibly the density of tubule interconnections (PubMed:23969831). Acts as an adapter protein and facilitates the interaction of KIF5A with VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 and the ZFYVE27-KIF5A complex contributes to the transport of these proteins in neurons. Can induce formation of neurite-like membrane protrusions in non-neuronal cells in a KIF5A/B-dependent manner (PubMed:21976701). {ECO:0000250|UniProtKB:Q3TXX3, ECO:0000269|PubMed:17082457, ECO:0000269|PubMed:19289470, ECO:0000269|PubMed:21976701, ECO:0000269|PubMed:23969831, ECO:0000269|PubMed:24668814}.;
Disease: DISEASE: Spastic paraplegia 33, autosomal dominant (SPG33) [MIM:610244]: 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. {ECO:0000269|PubMed:16826525, ECO:0000269|PubMed:18606302, ECO:0000269|PubMed:23969831, ECO:0000269|PubMed:24668814}. Note=The disease is caused by mutations affecting the gene represented in this entry. According to PubMed:18606302, the properties of the variant Val-191 and its frequency in some populations raise doubts on the implication of that gene in the disease.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.350
RVIS EVS: 0.87
RVIS percentile EVS: 88.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.443

Gene Damage Prediction

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