FLI1

Chr 11ADAR

Fli-1 proto-oncogene, ETS transcription factor

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

NCBI Gene: 2313 ENSG00000151702 UniProt: Q01543 OMIM: 193067

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.281 OMIM phenotype

Clinical Summary— FLI1

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Gene-Disease Validity (ClinGen)

bleeding disorder, platelet-type, 21 · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 118 VUS of 308 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.3892th %ile

GOF

0.3094th %ile

LOF

0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.28

Literature Evidence

LOFFli1 haploinsufficiency underlies Paris-Trousseau thrombopenia1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 15525489 ↗

ClinVar Variant Classifications

308 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic7

VUS118

Likely Benign108

Benign44

Conflicting6

Pathogenic

Likely Pathogenic

118

VUS

108

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	1	0	5
Likely Pathogenic	4	2	1	0	7
VUS	6	108	4	0	118
Likely Benign	0	1	30	77	108
Benign	0	0	39	5	44
Conflicting	—				6
Total	12	113	75	82	288

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

79 pathogenic / likely-pathogenic (of 89) ClinVar copy-number / structural variants overlap FLI1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →