FZD4

frizzled class receptor 4, the group of CD molecules|G protein-coupled receptors, Class F frizzled

Basic information

Region (hg38): 11:86945678-86955395

Previous symbols: [ "EVR1" ]

Links

ENSG00000174804 ∙ NCBI:8322 ∙ OMIM:604579 ∙ HGNC:4042 ∙ Uniprot:Q9ULV1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• exudative vitreoretinopathy (Supportive), mode of inheritance: AD
• persistent hyperplastic primary vitreous (Supportive), mode of inheritance: AD
• exudative vitreoretinopathy 1 (Definitive), mode of inheritance: AD
• exudative vitreoretinopathy 1 (Strong), mode of inheritance: AD
• exudative vitreoretinopathy 1 (Limited), mode of inheritance: Unknown
• exudative vitreoretinopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Exudative vitreoretinopathy 1	AD/Digenic	General	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	Ophthalmologic	12172548; 14507768; 15488808; 15981244; 21097938
Digenic inheritance (with LRP5 has been reported)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FZD4 gene.

• not provided (299 variants)
• Exudative vitreoretinopathy 1 (135 variants)
• Familial exudative vitreoretinopathy (13 variants)
• Inborn genetic diseases (9 variants)
• not specified (4 variants)
• Exudative retinopathy;Familial exudative vitreoretinopathy (2 variants)
• Retinal dystrophy (2 variants)
• Atrophia bulborum hereditaria (1 variants)
• Retinopathy of prematurity (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FZD4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	63	2	70
missense	5	8	153	9	2	177
nonsense	10	2				12
start loss						0
frameshift	23	5	3			31
inframe indel	1	1	3			5
splice donor/acceptor (+/-2bp)	1					1
splice region				1		1
non coding			65	11	43	119
Total	40	16	229	83	47

Highest pathogenic variant AF is 0.0000460

Variants in FZD4

This is a list of pathogenic ClinVar variants found in the FZD4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-86945691-C-T		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86945774-G-A		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86945858-GAA-G		Familial exudative vitreoretinopathy	Likely benign (Jun 14, 2016)
11-86945886-C-T		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)
11-86945891-GA-G		Familial exudative vitreoretinopathy	Uncertain significance (Jun 14, 2016)
11-86945974-G-C		Exudative vitreoretinopathy 1	Uncertain significance (Feb 12, 2018)
11-86946065-G-C		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86946259-C-A		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86946275-T-C		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)
11-86946367-G-A		Exudative vitreoretinopathy 1	Benign (Jan 12, 2018)
11-86946377-A-G		Exudative vitreoretinopathy 1	Benign (Jan 12, 2018)
11-86946386-C-G		Exudative vitreoretinopathy 1	Uncertain significance (Feb 12, 2018)
11-86946464-T-C		Exudative vitreoretinopathy 1	Uncertain significance (Jan 12, 2018)
11-86946478-A-G		Exudative vitreoretinopathy 1	Benign (Jan 12, 2018)
11-86946524-C-T		Exudative vitreoretinopathy 1	Benign (Jan 12, 2018)
11-86946624-G-C		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86946626-G-A		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)
11-86946728-A-G		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)
11-86946756-A-C		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)
11-86946807-A-G		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86946946-T-C		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86946971-T-A		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)
11-86947059-T-G		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)
11-86947063-C-T		Exudative vitreoretinopathy 1	Benign (Jan 13, 2018)
11-86947073-C-T		Exudative vitreoretinopathy 1	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FZD4	protein_coding	protein_coding	ENST00000531380	2	9713

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.970	0.0304	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.733	255	290	0.879	0.0000149	3512
Missense in Polyphen		62	101.43	0.61127		1320
Synonymous	-0.567	121	113	1.07	0.00000610	1081
Loss of Function	3.38	1	15.2	0.0657	6.63e-7	207

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000277	0.000277
European (Non-Finnish)	0.0000452	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.
• Disease: DISEASE: Vitreoretinopathy, exudative 1 (EVR1) [MIM:133780]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. In many ways the disease resembles retinopathy of prematurity but there is no evidence of prematurity or small birth weight in the patient history. {ECO:0000269|PubMed:12172548, ECO:0000269|PubMed:14507768, ECO:0000269|PubMed:15035989, ECO:0000269|PubMed:15223780, ECO:0000269|PubMed:15370539, ECO:0000269|PubMed:15488808, ECO:0000269|PubMed:15733276, ECO:0000269|PubMed:15981244, ECO:0000269|PubMed:17093393, ECO:0000269|PubMed:17955262, ECO:0000269|PubMed:19172507, ECO:0000269|PubMed:19324841, ECO:0000269|PubMed:20340138}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Gastric cancer - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Breast cancer - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Basal cell carcinoma - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);WNT-Core;Mesodermal Commitment Pathway;Ectoderm Differentiation;Association Between Physico-Chemical Features and Toxicity Associated Pathways;ESC Pluripotency Pathways;Wnt Signaling Pathway and Pluripotency;Wnt Signaling in Kidney Disease;EMT transition in Colorectal Cancer;Signaling by GPCR;Signaling by WNT;Signal Transduction;Vesicle-mediated transport;Membrane Trafficking;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Regulation of FZD by ubiquitination;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;Clathrin-mediated endocytosis;Asymmetric localization of PCP proteins;WNT5A-dependent internalization of FZD4;PCP/CE pathway;Ca2+ pathway;Beta-catenin independent WNT signaling;Cargo recognition for clathrin-mediated endocytosis;GPCR signaling-G alpha i;Wnt;Wnt Canonical;Wnt signaling network;TCF dependent signaling in response to WNT;Wnt Mammals (Consensus)

Recessive Scores

• pRec: 0.210

Intolerance Scores

• loftool: 0.0584
• rvis_EVS: -0.33
• rvis_percentile_EVS: 30.7

Haploinsufficiency Scores

• pHI: 0.349
• hipred: Y
• hipred_score: 0.699
• ghis: 0.542

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.961

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fzd4
• Phenotype: muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; reproductive system phenotype; normal phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; vision/eye phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; pigmentation phenotype

Gene ontology

• Biological process: vasculogenesis;G protein-coupled receptor signaling pathway;Wnt signaling pathway, calcium modulating pathway;sensory perception of sound;negative regulation of cell-substrate adhesion;Wnt signaling pathway;neuron differentiation;regulation of vascular endothelial growth factor receptor signaling pathway;locomotion involved in locomotory behavior;substrate adhesion-dependent cell spreading;extracellular matrix-cell signaling;non-canonical Wnt signaling pathway;progesterone secretion;positive regulation of JUN kinase activity;positive regulation of transcription, DNA-templated;positive regulation of DNA-binding transcription factor activity;canonical Wnt signaling pathway;Wnt signaling pathway, planar cell polarity pathway;membrane organization;retina vasculature morphogenesis in camera-type eye;cerebellum vasculature morphogenesis;retinal blood vessel morphogenesis;cellular response to retinoic acid;positive regulation of neuron projection arborization;cellular response to leukemia inhibitory factor
• Cellular component: plasma membrane;integral component of plasma membrane;cell-cell junction;cell surface;dendrite;clathrin-coated vesicle membrane;clathrin-coated endocytic vesicle membrane;glutamatergic synapse
• Molecular function: amyloid-beta binding;G protein-coupled receptor activity;protein binding;Wnt-protein binding;cytokine binding;PDZ domain binding;ubiquitin protein ligase binding;signaling receptor activity;protein homodimerization activity;Wnt-activated receptor activity;protein-containing complex binding;protein heterodimerization activity