FLI1

Chr 11

Fli-1 proto-oncogene, ETS transcription factor

Also known as: BDPLT21, EWSR2, FLI-1, SIC-1

NCBI Gene: 2313 ENSG00000151702 UniProt: Q01543

FLI1 encodes a transcription factor with an ETS DNA-binding domain that functions as a sequence-specific transcriptional activator. Mutations cause bleeding disorder, platelet-type, 21, inherited in both autosomal dominant and autosomal recessive patterns. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.28), indicating intolerance to functional disruption.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transcription factor containing an ETS DNA-binding domain. The gene can undergo a t(11;22)(q24;q12) translocation with the Ewing sarcoma gene on chromosome 22, which results in a fusion gene that is present in the majority of Ewing sarcoma cases. An acute lymphoblastic leukemia-associated t(4;11)(q21;q23) translocation involving this gene has also been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtEwing sarcoma

UniProtBleeding disorder, platelet-type, 21

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · bleeding disorder, platelet-type, 21 · AD · ClinGen 2023

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

258

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

LOF

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

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.989

Z-score 4.00

OE 0.09 (0.04–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.40Z-score

OE missense 0.59 (0.52–0.68)

164 obs / 276.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.28)

0≤0.351.4

Missense OE?0.59 (0.52–0.68)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 2 / 22.5Missense obs/exp: 164 / 276.4Syn Z: -0.79

Background carrier burden — how many people carry a rare variant somewhere in FLI1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

480 rare PASS variants

Rare truncating (LoF)

1 in 7,800

28 rare PASS variants

Rare synonymous (reference)

1 in 140

273 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FLI1. 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 200	1 in 10,000
South Asian	~43k	1 in 120	1 in 2,200
Remaining (unassigned)	~30k	1 in 140	≈ 1 in 7,400
European (Finnish)	~27k	1 in 640	≈ 1 in 27,000
Admixed American	~22k	1 in 140	≈ 1 in 22,000
African / African American	~21k	1 in 140	≈ 1 in 17,000
East Asian	~20k	1 in 170	1 in 2,000
Ashkenazi Jewish	~13k	1 in 420	none seen
Middle Eastern	~2,884	1 in 180	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): 7 of 9 coding exons well covered in gnomAD exomes; exons 1, 6 marginal. Genomes: all 9.? see exons ↓