FZD3

Chr 8

frizzled class receptor 3

Also known as: Fz-3

NCBI Gene: 7976 ENSG00000104290 UniProt: Q9NPG1

The FZD3 protein is a seven-transmembrane receptor for Wnt signaling proteins that controls axon growth and guidance during development of major central nervous system fiber tracts including the corpus callosum, corticospinal tract, and thalamocortical connections, as well as peripheral motor nerves and neural tube closure. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, intellectual disability, seizures, and structural brain abnormalities including agenesis of the corpus callosum. This gene is highly intolerant to loss-of-function mutations, indicating that complete loss of protein function is likely pathogenic.

ResearchSummary from RefSeq, UniProt

This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. The function of this protein is unknown, although it may play a role in mammalian hair follicle development. Alternative splicing results in multiple transcript variants. This gene is a susceptibility locus for schizophrenia. [provided by RefSeq, Dec 2010]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.62

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.000

Z-score 3.14

OE 0.37 (0.23–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.64Z-score

OE missense 0.62 (0.56–0.69)

240 obs / 385.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.37 (0.23–0.62)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 11 / 29.4Missense obs/exp: 240 / 385.7Syn Z: 0.29

Background carrier burden — how many people carry a rare variant somewhere in FZD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

649 rare PASS variants

Rare truncating (LoF)

1 in 2,900

59 rare PASS variants

Rare synonymous (reference)

1 in 170

269 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FZD3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 2,500
South Asian	~43k	1 in 160	1 in 3,100
Remaining (unassigned)	~30k	1 in 140	1 in 2,300
European (Finnish)	~27k	1 in 670	1 in 3,800
Admixed American	~22k	1 in 110	≈ 1 in 5,600
African / African American	~21k	1 in 100	1 in 2,800
East Asian	~20k	1 in 200	1 in 2,100
Ashkenazi Jewish	~13k	1 in 370	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 170	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 6 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 6.? see exons ↓