FGFRL1

Chr 4

fibroblast growth factor receptor like 1

Also known as: FGFR-5, FGFR5, FHFR

NCBI Gene: 53834 ENSG00000127418 UniProt: Q8N441 OMIM: 605830

The encoded protein is a transmembrane receptor that lacks the typical cytoplasmic tyrosine kinase domain found in other fibroblast growth factor receptors and has a negative effect on cell proliferation. Mutations cause Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis, inherited in an autosomal recessive pattern. The syndrome involves craniofacial malformations, skeletal abnormalities, and steroidogenic defects present from birth.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. A marked difference between this gene product and the other family members is its lack of a cytoplasmic tyrosine kinase domain. The result is a transmembrane receptor that could interact with other family members and potentially inhibit signaling. Multiple alternatively spliced transcript variants encoding the same isoform have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.73

Clinical Summary— FGFRL1

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.012

Z-score 2.35

OE 0.37 (0.20–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.25Z-score

OE missense 0.96 (0.88–1.05)

341 obs / 354.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.20–0.73)

0≤0.351.4

Missense OE?0.96 (0.88–1.05)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 6 / 16.2Missense obs/exp: 341 / 354.1Syn Z: -2.30

This gene — mechanism propensity

0.75top 25%

GOF

0.6834th %ile

LOF

0.4430th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.