FGF12

Chr 3AD

fibroblast growth factor 12

Also known as: DEE47, EIEE47, FGF12B, FHF1

NCBI Gene: 2257 ENSG00000114279 UniProt: P61328 OMIM: 601513

The protein is a member of the fibroblast growth factor family that lacks a signal sequence and instead localizes to the nucleus rather than being secreted. Mutations cause developmental and epileptic encephalopathy 47 through an autosomal dominant inheritance pattern. The specific mechanism by which nuclear FGF12 dysfunction leads to seizures and developmental delay remains unclear.

OMIM 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 growth factor lacks the N-terminal signal sequence present in most of the FGF family members, but it contains clusters of basic residues that have been demonstrated to act as a nuclear localization signal. When transfected into mammalian cells, this protein accumulated in the nucleus, but was not secreted. The specific function of this gene has not yet been determined. [provided by RefSeq, Dec 2019]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 47MIM #617166

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.54

LOEUF

GOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.623

Z-score 2.63

OE 0.17 (0.07–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.52Z-score

OE missense 0.64 (0.54–0.76)

91 obs / 142.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.07–0.54)

0≤0.351.4

Missense OE?0.64 (0.54–0.76)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 2 / 11.7Missense obs/exp: 91 / 142.1Syn Z: 0.45

Background carrier burden — how many people carry a rare variant somewhere in FGF12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 670

261 rare PASS variants

Rare truncating (LoF)

1 in 15,000

35 rare PASS variants

Rare synonymous (reference)

1 in 490

121 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FGF12. 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 720	1 in 12,000
South Asian	~43k	1 in 630	≈ 1 in 21,000
Remaining (unassigned)	~30k	1 in 400	≈ 1 in 29,000
European (Finnish)	~27k	1 in 1,500	≈ 1 in 13,000
Admixed American	~22k	1 in 610	≈ 1 in 5,400
African / African American	~21k	1 in 470	none seen
East Asian	~20k	1 in 430	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 6,500	none seen
Middle Eastern	~2,884	1 in 580	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): 4 of 5 coding exons well covered in gnomAD exomes; exon 6 marginal. Genomes: all 5.? see exons ↓