WNT3

protein-coding

Wnt family member 3, the group of Wnt family

Gene summary

The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family. It encodes a protein which shows 98% amino acid identity to mouse Wnt3 protein, and 84% to human WNT3A protein, another WNT gene product. The mouse studies show the requirement of Wnt3 in primary axis formation in the mouse. Studies of the gene expression suggest that this gene may play a key role in some cases of human breast, rectal, lung, and gastric cancer through activation of the WNT-beta-catenin-TCF signaling pathway. This gene is clustered with WNT15, another family member, in the chromosome 17q21 region. [provided by RefSeq, Jul 2008]

Previous symbols:

INT4

MANE transcript

NM_030753.5

Inheritance

ClinVar variants

P:2U:52B:49

Top phenotype

Tetraamelia syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr17:46,762,506-46,833,154

External References & Databases

Ensembl (ENSG00000108379)

Transcript & Mutation Effects

hg38 • Region Span ~70.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

tetraamelia syndrome 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0060764

Submitter: Genomics England PanelApp

tetraamelia-multiple malformations syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010110

Submitter: Orphanet

tetraamelia syndrome 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060764

Submitter: PanelApp Australia

tetraamelia syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060764

Submitter: G2P

tetraamelia syndrome 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0060764

Submitter: ClinGen

The *WNT3* gene is located on chromosome 17 at 17q32.32 and encodes Wnt family member 3 (*WNT3*), a signalling protein within the Wnt/b-catenin signalling pathways. *WNT3* was first reported in relation to autosomal recessive tetra-amelia syndrome 1 in 2004 (PMID: 14872406). Tetra-amelia syndrome is characterized by the complete absence of all four limbs with additional multisystem malformations. Evidence supporting this gene-disease relationship includes case-level data and experimental evidence. To date, the disorder has been reported in a single consanguineous family of Aramaic descent. The disorder was diagnosed prenatally in four affected fetuses which were terminated between weeks 13 and 20 of gestation. Positional cloning identified a homozygous stop-gain variant c.247C>T p.(Gln83Ter) in the affected fetuses. The mechanism of pathogenicity is presumed to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (expression and mouse model evidence). The gene disease association is supported by a spatial and temporal expression pattern in the developing mouse embryo which is consistent with the clinical phenotype (PMID: 12569130). Both targeted and conditional knockout mouse models support a crucial role for *WNT3* during embryogenesis and limb formation, recapitulating aspects of the phenotype spectrum associated with tetra-amelia syndrome 1 (PMID: 12569130, 10431240). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic disorders GCEP on the meeting date 16th May 2025 (SOP Version 11).

tetraamelia syndrome 1LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0060764

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Tetraamelia syndrome 1AR

Manifestation: Craniofacial; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal; Renal

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: 14872406

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WNT3 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 118

not specifiedTotal: 27

WNT3-related disorderTotal: 4

Bladder exstrophy-epispadias-cloacal exstrophy complexTotal: 2

Tetraamelia syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030753.5. 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			2 clinvar	48 clinvar	1 clinvar	51
missense		1 clinvar	50 clinvar			51
nonsense	1 clinvar					1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	1	52	48	1	103

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030753.5	RefSeq	NP_110380.1	4	MANE Select
ENST00000225512.6	Ensembl	ENSP00000225512.5	4	MANE Select
ENST00000706483.1	Ensembl	ENSP00000516407.1	2	Standard
ENST00000706484.1	Ensembl	ENSP00000516408.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
wnt3	Danio rerio	Structure: cloaca Quality: increased width abnormal

Gene / Model

Organism

Observed Phenotype

wnt3

Danio rerio

Structure: cloaca

Quality: increased width

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

cell morphogenesis
mesoderm formation
gamete generation
axon guidance
anterior/posterior axis specification

Molecular Function

frizzled binding
protein binding
protein domain specific binding
receptor ligand activity

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum lumen
Golgi lumen
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000225512
Coding exons: 4
Length: 70649
Individuals with no LoFs: 122322
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 122323
p: 0.00000409

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.18	109	251	0.435	0.0000184	2313
Missense (PolyPhen)		30	99.567	0.3013		918
Synonymous	0.595	106	114	0.929	0.00000937	706
Loss of Function	3.19	2	15.6	0.128	7.59e-7	157

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00020	0.00010	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ligand for members of the frizzled family of seven transmembrane receptors (Probable). Functions in the canonical Wnt signaling pathway that results in activation of transcription factors of the TCF/LEF family (PubMed:26902720). Required for normal gastrulation, formation of the primitive streak, and for the formation of the mesoderm during early embryogenesis. Required for normal formation of the apical ectodermal ridge (By similarity). Required for normal embryonic development, and especially for limb development (PubMed:14872406). {ECO:0000250|UniProtKB:P17553, ECO:0000269|PubMed:14872406, ECO:0000269|PubMed:26902720, ECO:0000305}.;
Disease: DISEASE: Tetraamelia syndrome 1 (TETAMS1) [MIM:273395]: A form of tetraamelia, a rare disease characterized by rudimentary appendages or complete absence of all four limbs, and other anomalies such as craniofacial, nervous system, pulmonary, skeletal and urogenital defects. TETAMS1 patients manifest complete limb agenesis without defects of scapulae or clavicles. Other features include bilateral cleft lip/palate, diaphragmatic defect with bilobar right lung, renal and adrenal agenesis, pelvic hypoplasia, and urogenital defects. TETAMS1 transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:14872406}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.270

Intolerance Scores

LoFtool: 0.0728
RVIS EVS: -0.45
RVIS percentile EVS: 24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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