WNT5A

protein-coding

Wnt family member 5A, 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 encodes a member of the WNT family that signals through both the canonical and non-canonical WNT pathways. This protein is a ligand for the seven transmembrane receptor frizzled-5 and the tyrosine kinase orphan receptor 2. This protein plays an essential role in regulating developmental pathways during embryogenesis. This protein may also play a role in oncogenesis. Mutations in this gene are the cause of autosomal dominant Robinow syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

MANE transcript

NM_003392.7

Inheritance

ClinVar variants

P:14U:155B:86

Top phenotype

Robinow syndrome, autosomal dominant 1

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr3:55,465,715-55,490,539

External References & Databases

Ensembl (ENSG00000114251)

Transcript & Mutation Effects

hg38 • Region Span ~24.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant Robinow syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024455

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant Robinow syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008389

Submitter: Orphanet

autosomal dominant Robinow syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024455

Submitter: PanelApp Australia

autosomal dominant Robinow syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008389

Submitter: ClinGen

The WNT5A gene is located on chromosome 3 at 3p14.3 and encodes the Wnt family member 5A protein, which is a ligand for members of the frizzled family of seven transmembrane receptors, and is involved in both the canonical and noncanonical signaling pathways, depending upon the receptor context. WNT proteins play an essential role during development, controlling processes such as embryonic patterning, cell growth, migration, and differentiation. The WNT5A gene was first reported in relation to autosomal dominant Robinow syndrome in 2010 (Person et al., PMID 19918918). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands from four publications (Person et al., 2010 PMID 19918918; Roifman et al., 2015 PMID 24716670; Xiong et al., 2016 PMID 27092434; White et al., 2018 PMID 29276006). Variants in this gene segregate with disease in approximately nine family members from three families. As a result of this re-evaluation, five additional variants in six probands (one duplication and four missense variants) reported in four publications (PMIDs: 34627339. 35047859, 35586607, 34750320) have been included in this curation. The mechanism of disease has not been clearly defined, but missense variants were most commonly reported, with functional data for two of the missense variants suggesting they are hypomorphic (Person et al., 2010 PMID 19918918). Of note, there is one report of an autosomal recessive form of Robinow syndrome caused by a homozygous frameshift variant in WNT5A, resulting in perinatal death (Birgmeier et al., 2018 PMID 29575632). This gene-disease relationship is supported by expression data, biochemical function data, a knockout mouse model and a chick embryo limb model expressing a WNT5A variant found in a proband (Yamaguchi et al., 1999 PMID 10021340; Oishi et al., 2003 PMID 12839624; Mikels and Nusse, 2006 PMID 16602827; Gignac et al., 2019 PMID 31032853). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on October 27th, 2020 (SOP Version 8). This GDR was re-evaluated on April 25th, 2024 (SOP Version 10). Although new genetic evidence was published (PMIDs: 34627339. 35047859, 35586607, 34750320), the classification did not change.

autosomal dominant Robinow syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0024455

Submitter: G2P

autosomal dominant Robinow syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0024455

Submitter: Illumina

The WNT5A gene is located on chromosome 3 at 3p14.3 and encodes Wnt family member 5A, which is a ligand for members of the frizzled family of seven transmembrane receptors and is involved in both the canonical and noncanonical signaling pathways, depending upon the receptor context. WNT proteins play an essential role during development, controlling processes such as embryonic patterning, cell growth, migration, and differentiation. The WNT5A gene was first reported in relation to autosomal dominant Robinow syndrome in 2010 (19918918: Person et al. 2010). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in four publications (19918918: Person et al. 2010; 24716670: Roifman et al. 2015; 27092434: Xiong et al. 2016; 29276006: White et al. 2018). Variants in this gene segregated with disease in approximately nine additional family members. The mechanism of disease has not been clearly defined, but missense variants were most commonly reported, and functional data for two suggested they were hypomorphic (19918918: Person et al. 2010). This gene-disease relationship is supported by expression and biochemical function data as well as a knock out mouse model (10021340: Yamaguchi et al. 1999; 12839624: Oishi et al. 2003; 16602827: Mikels and Nusse 2006). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

autosomal dominant Robinow syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0024455

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Robinow syndrome, autosomal dominant 1AD

Manifestation: Craniofacial; Dental; Genitourinary; Musculoskeletal; Renal

Intervention: Renal

Rationale: Individuals have been described with high-grade vesicoureteral reflux, and surveillance and management may be helpful to preserve renal function

Refs: 5771504; 3746837; 17256787; 19918918; 24716670

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WNT5A variants in ClinVar

8 Conditions Cataloged

not providedTotal: 213

Autosomal dominant Robinow syndrome 1Total: 74

Inborn genetic diseasesTotal: 42

WNT5A-related disorderTotal: 25

not specifiedTotal: 22

Short statureTotal: 1

Autosomal dominant Robinow syndromeTotal: 1

Leukoencephalopathy, motor delay, spasticity, and dysarthria syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003392.7. 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			6 clinvar	60 clinvar	2 clinvar	68
missense	3 clinvar	10 clinvar	143 clinvar	18 clinvar	6 clinvar	180
nonsense						0
start loss			1 clinvar			1
frameshift		1 clinvar	3 clinvar			4
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	11	155	78	8	255

Highest pathogenic variant AF is 7.6715475e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003392.7	RefSeq	NP_003383.4	5	MANE Select
ENST00000264634.9	Ensembl	ENSP00000264634.4	5	MANE Select
NM_001256105.1	RefSeq	NP_001243034.1	4	Standard
NM_001377271.1	RefSeq	NP_001364200.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
wnt5a	Danio rerio	Structure: perichondrium Quality: edematous abnormal

Gene / Model

Organism

Observed Phenotype

wnt5a

Danio rerio

Structure: perichondrium

Quality: edematous

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

activation of MAPK activity
establishment of planar polarity
somitogenesis
epithelial to mesenchymal transition
positive regulation of endothelial cell proliferation

Molecular Function

DNA-binding transcription factor activity
frizzled binding
receptor tyrosine kinase-like orphan receptor binding
cytokine activity
protein binding

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: ENST00000474267
Coding exons: 5
Length: 24231
Individuals with no LoFs: 124736
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124737
p: 0.00000401

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.98	159	246	0.645	0.0000167	2480
Missense (PolyPhen)		42	105.92	0.39653		962
Synonymous	0.587	96	104	0.927	0.00000786	716
Loss of Function	3.67	1	17.6	0.0568	9.05e-7	189

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
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. Can activate or inhibit canonical Wnt signaling, depending on receptor context. In the presence of FZD4, activates beta-catenin signaling. In the presence of ROR2, inhibits the canonical Wnt pathway by promoting beta-catenin degradation through a GSK3-independent pathway which involves down-regulation of beta-catenin-induced reporter gene expression (By similarity). Suppression of the canonical pathway allows chondrogenesis to occur and inhibits tumor formation. Stimulates cell migration. Decreases proliferation, migration, invasiveness and clonogenicity of carcinoma cells and may act as a tumor suppressor (PubMed:15735754). Mediates motility of melanoma cells (PubMed:17426020). Required during embryogenesis for extension of the primary anterior-posterior axis and for outgrowth of limbs and the genital tubercle. Inhibits type II collagen expression in chondrocytes (By similarity). {ECO:0000250|UniProtKB:P22725, ECO:0000250|UniProtKB:Q27Q52, ECO:0000269|PubMed:15735754, ECO:0000269|PubMed:17426020}.;
Disease: DISEASE: Robinow syndrome, autosomal dominant 1 (DRS1) [MIM:180700]: A disease characterized by short-limb dwarfism, costovertebral segmentation defects and abnormalities of the head, face and external genitalia. The clinical signs are generally milder in dominant cases. {ECO:0000269|PubMed:19918918}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.637

Intolerance Scores

RVIS EVS: -0.16
RVIS percentile EVS: 41.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
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