WNT5A

Chr 3

Wnt family member 5A

Also known as: hWNT5A

NCBI Gene: 7474 ENSG00000114251 UniProt: P41221

WNT5A encodes a secreted signaling protein that serves as a ligand for frizzled receptors and can either activate or inhibit canonical Wnt signaling depending on receptor context, playing essential roles in embryonic axis extension, limb outgrowth, and chondrogenesis. Mutations cause autosomal dominant Robinow syndrome, which involves skeletal abnormalities and distinctive facial features. This gene is highly constrained against loss-of-function variation (pLI 0.99), indicating that such variants are likely to be pathogenic.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

LOEUF 0.27

Clinical Summary— WNT5A

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Gene-Disease Validity (ClinGen)

autosomal dominant Robinow syndrome · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 148 VUS of 307 total submissions

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GeneReview available — WNT5A

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.987

Z-score 3.67

OE 0.06 (0.02–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.98Z-score

OE missense 0.65 (0.57–0.74)

159 obs / 246.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.27)

0≤0.351.4

Missense OE?0.65 (0.57–0.74)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 1 / 17.6Missense obs/exp: 159 / 246.5Syn Z: 0.59

ClinVar Variant Classifications

307 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic9

VUS148

Likely Benign98

Benign22

Conflicting22

Pathogenic

Likely Pathogenic

148

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	9	0	0	9
VUS	4	132	7	5	148
Likely Benign	0	7	37	54	98
Benign	0	6	13	3	22
Conflicting	—				22
Total	4	157	57	62	302

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

5 pathogenic / likely-pathogenic (of 6) ClinVar copy-number / structural variants overlap WNT5A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →