FGF4

Chr 11

fibroblast growth factor 4

Also known as: FGF-4, HBGF-4, HST, HST-1, HSTF-1, HSTF1, K-FGF, KFGF

NCBI Gene: 2249 ENSG00000075388 UniProt: P08620

This gene encodes fibroblast growth factor 4, which regulates embryonic development, cell proliferation, and cell differentiation, and is required for normal limb and cardiac valve development. Mutations cause short-rib thoracic dysplasia 22 without polydactyly, a congenital skeletal disorder affecting the thorax and ribs. The condition follows autosomal recessive inheritance.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtShort-rib thoracic dysplasia 22 without polydactyly

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.09

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?

1.09LOEUF

pLI 0.141

Z-score 1.45

OE 0.35 (0.14–1.09)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.00Z-score

OE missense 0.71 (0.59–0.87)

69 obs / 96.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.14–1.09)

0≤0.351.4

Missense OE?0.71 (0.59–0.87)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 2 / 5.8Missense obs/exp: 69 / 96.8Syn Z: 0.09

Background carrier burden — how many people carry a rare variant somewhere in FGF4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 330

309 rare PASS variants

Rare truncating (LoF)

1 in 7,200

29 rare PASS variants

Rare synonymous (reference)

1 in 200

170 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FGF4. 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 430	1 in 6,100
South Asian	~43k	1 in 200	≈ 1 in 16,000
Remaining (unassigned)	~30k	1 in 190	≈ 1 in 30,000
European (Finnish)	~27k	1 in 450	≈ 1 in 16,000
Admixed American	~22k	1 in 240	1 in 2,200
African / African American	~21k	1 in 210	≈ 1 in 6,500
East Asian	~20k	1 in 390	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 660	none seen
Middle Eastern	~2,884	1 in 270	≈ 1 in 2,900

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): 2 of 3 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 3.? see exons ↓