FOSL1

Chr 11

FOS like 1, AP-1 transcription factor subunit

Also known as: FRA, FRA1, fra-1

NCBI Gene: 8061 ENSG00000175592 UniProt: P15407 OMIM: 136515

The FOSL1 protein is a leucine zipper transcription factor that dimerizes with JUN family proteins to form the AP-1 transcription factor complex, which regulates cell proliferation, differentiation, and transformation. Mutations in FOSL1 cause autosomal dominant premature craniosynostosis, a condition where skull sutures fuse too early during infancy. The gene shows moderate constraint against loss-of-function variants, and the craniosynostotic phenotype typically manifests in early infancy.

OMIM ResearchSummary from RefSeq

The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

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

154

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.75

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.158

Z-score 2.12

OE 0.29 (0.13–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.40Z-score

OE missense 0.91 (0.79–1.05)

142 obs / 155.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.13–0.75)

0≤0.351.4

Missense OE?0.91 (0.79–1.05)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 3 / 10.4Missense obs/exp: 142 / 155.9Syn Z: 1.01

Background carrier burden — how many people carry a rare variant somewhere in FOSL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

366 rare PASS variants

Rare truncating (LoF)

1 in 420

41 rare PASS variants

Rare synonymous (reference)

1 in 620

119 rare PASS variants

Rare missense and truncating variants are carried at similar rates in FOSL1; this gene does not show strong loss-of-function constraint by this measure. 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 220	1 in 1,900
South Asian	~43k	1 in 130	1 in 1,300
Remaining (unassigned)	~30k	1 in 120	1 in 3,800
European (Finnish)	~27k	1 in 1,200	1 in 1,300
Admixed American	~22k	1 in 150	1 in 2,700
African / African American	~21k	1 in 180	1 in 2,700
East Asian	~20k	1 in 200	≈ 1 in 7,700
Ashkenazi Jewish	~13k	≈ 1 in 3,300	none seen
Middle Eastern	~2,884	1 in 180	≈ 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): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓