FLI1
protein-codingFli-1 proto-oncogene, ETS transcription factor, the group of ETS transcription factor family
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~126.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0054577
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0054577
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0054577
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0054577
Submitter: ClinGen
FLI1 gene was first reported in relation to autosomal dominant bleeding disorder, platelet-type, 21 in 2013 (Stockley J, et al., PMID: 24100448). At least six unique variants (five missense, one frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands in three publications (PMIDs: 24100448, 28255014, 28748566). In addition, Dr. Juliana Perez Botero contribute four independent cases from three families (personal communications, from Versiti Diagnostic Laboratory Cohort). Two patients (mother and the son) carry the c.892delA (p.Ser298fs) variant, which is not reported in the literature. The other two patients carry the c.1010G>A(p.Arg337Gln) and c.1028A>G (p.Tyr343Cys) respectively and these two variants have been reported before. Also, Dr. Kate Downes has contributed an independent case of a female born in 2006 who presented with Macrothrombocytopenia. The proband carries a truncating variant NM_002017.5(FLI1):c.946G>T (p.Glu316Ter), listed in ClinVar (ClinVar Record). In the test order form, ACTN1, FLNA, TUBB1, and MYH9 were considered as likely candidates. This gene-disease relationship is also supported by its expression evidence that FLI1 preferentially expresses in hematopoietic cells (PMID: 8439553) and functional alteration in both patient cells (PMID: 28255014) and non-patient cells(PMID: 28255014). Additionally, there are 2 FLI1 insufficient cell models, which are the induced-pluripotent stem cell (iPSC)–derived megakaryocytes (iMegs), generated from a patient with PTSx and iPSCs from a control line with a targeted heterozygous FLI1 knockout (FLI1 +/-), the authors showed that the heterozygous FLI1 loss resulted in the megakaryocyte and platelet defects. In addition, patients with deletions of 11q23 who were confirmed to be heterozygous for a deletion of the FLI1 gene presented with giant alpha-granules on peripheral blood smear and dysmegakaryopoiesis with many micromegakaryocytes on bone marrow examination. Clinical characteristics in addition to thrombocytopenia included mental retardation, facial dysmorphism, clinodactyly, and pyloric stenosis (PMID: 14597985) and these patients, with multi-gene deletions, were not considered within this gene-disease relationship though mouse models and iPSCs derived megakaryocytes (iMegs) suggested that the heterozygous loss of FLI gene was responsible for the dysmegakaryopoiesis in these patients (PubMed: 10981960, 28432223). In summary, there is moderate evidence to support this gene-disease relationship. This classification was originally approved by the ClinGen Hemostasis Thrombosis Gene Curation Expert Panel on April 28, 2021. This gene-disease relationship was reevaluated on September 06, 2023. As a result of this reevaluation, the classification did not change.
Inheritance Pattern: AR
Disease ID:MONDO:0054577
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0054577
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals may have bleeding tendency, and precautions (eg, in surgical situations) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FLI1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002017.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 84 | 85 | |||
| missense | 2 | 5 | 111 | 4 | 122 | |
| nonsense | 1 | 1 | 2 | 4 | ||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 5 | 2 | 8 | ||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 4 | 11 | 122 | 88 | 0 | 225 |
Highest pathogenic variant AF is 0.000001859236
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002008.2 | 9 | MANE Select | |
| Ensembl | ENSP00000433488.2 | 9 | MANE Select | |
| RefSeq | NP_001161153.1 | 8 | Standard | |
| RefSeq | NP_001257939.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| fli1a | Danio rerio | Structure: head Quality: hemorrhagic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Transcriptional misregulation in cancer - Homo sapiens (human)
- Hematopoietic Stem Cell Differentiation
- FGF
Biological Process
- regulation of transcription by RNA polymerase II
- hemostasis
- blood circulation
- animal organ morphogenesis
- cell differentiation
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II distal enhancer sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
Cellular Component
- nucleus
- cytosol
- nuclear body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000527786
- Coding exons
- 9
- Length
- 126733
- Individuals with no LoFs
- 124926
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 124930
- p
- 0.0000160
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.40 | 164 | 276 | 0.593 | 0.0000169 | 2978 |
| Missense (PolyPhen) | 51 | 111.98 | 0.45542 | 1167 | ||
| Synonymous | -0.785 | 131 | 120 | 1.09 | 0.00000878 | 836 |
| Loss of Function | 4.00 | 2 | 22.5 | 0.0889 | 0.00000106 | 262 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000036 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Sequence-specific transcriptional activator (PubMed:24100448, PubMed:26316623, PubMed:28255014). Recognizes the DNA sequence 5'-C[CA]GGAAGT-3'. {ECO:0000269|PubMed:24100448, ECO:0000269|PubMed:26316623, ECO:0000269|PubMed:28255014}.;
- Disease
- DISEASE: Ewing sarcoma (ES) [MIM:612219]: A highly malignant, metastatic, primitive small round cell tumor of bone and soft tissue that affects children and adolescents. It belongs to the Ewing sarcoma family of tumors, a group of morphologically heterogeneous neoplasms that share the same cytogenetic features. They are considered neural tumors derived from cells of the neural crest. Ewing sarcoma represents the less differentiated form of the tumors. {ECO:0000269|PubMed:1522903, ECO:0000269|PubMed:1765382}. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving FLI1 is found in patients with Erwing sarcoma. Translocation t(11;22)(q24;q12) with EWSR1. {ECO:0000269|PubMed:1522903, ECO:0000269|PubMed:1765382}.; DISEASE: Bleeding disorder, platelet-type 21 (BDPLT21) [MIM:617443]: A disorder characterized by increased bleeding tendency due to platelet dysfunction. Clinical features include epistaxis, hematomas, bleeding after tooth extraction, and menorrhagia. BDPLT21 patients may have mild to moderate thrombocytopenia. {ECO:0000269|PubMed:24100448, ECO:0000269|PubMed:26316623, ECO:0000269|PubMed:28255014}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.368
- RVIS EVS
- -0.89
- RVIS percentile EVS
- 10.3
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.953
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |