GFI1B
protein-codinggrowth factor independent 1B transcriptional repressor, the group of Zinc fingers C2H2-type|MicroRNA protein coding host genes|SNAG transcriptional repressors
Gene summary
This gene encodes a zinc-finger containing transcriptional regulator that is primarily expressed in cells of hematopoietic lineage. The encoded protein complexes with numerous other transcriptional regulatory proteins including GATA-1, runt-related transcription factor 1 and histone deacetylases to control expression of genes involved in the development and maturation of erythrocytes and megakaryocytes. Mutations in this gene are the cause of the autosomal dominant platelet disorder, platelet-type bleeding disorder-17. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~47.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008553
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008553
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008553
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008553
Submitter: ClinGen
GFI1B was first reported in relation to Platelet-type bleeding disorder-17 in 2013 (Stevenson et al., PMID: 23927492). At least 9 unique variants including missense, nonsense, frameshift and splice site variants have been reported in humans. The GFI1B transcription factor is a member of the GFI zinc (Zn)-finger transcriptional repressor family which plays a pivotal role in hematopoiesis. Platelet-type bleeding disorder-17 is characterized by macrothrombocytopenia, a heterogeneous reduction of platelet alpha-granules in some cases associated with reduction of delta-granules, red cell anisopoikilocytosis, and a variable bleeding tendency. A consistent feature of the disease is that platelets express on their surface CD34. GFI1B variants reported to date cluster in the Zn-finger domain, with only three variants reported outside of this region. Large part of the patients reported are heterozygous for GF1B variants, and thus Platelet-type bleeding disorder-17 is considered autosomal dominant. However, 3 homozygous GFI1B variants have been reported. In PMID 28041820 the proband is homozygous for the p.Leu262Pro variant, the parents are carriers and do not express any phenotype. In 31249973 and PMID 28550182 the same individual is described, a female homozygous for the p.Ser185LeufsTer3 variant. The proband belongs to a large family in which the members homozygous for the variant express the phenotype while the heterozygous are healthy. Finally, in PMID 25258084 a patient is described homozygous for the p.Cys168Phe variant. We do not have any information about family members but in the same paper a patient heterozygous for the same variant is reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 9.9 Points. 9 variants in this gene have been reported in 11 probands in 9 publications (PMIDs: 31249973, 25258084, 28041820, 27122003, 24325358, 28880435, 28550182, 23927492, 28439885). Summary of Experimental Data: 4.5 Points This gene-disease association is supported by mouse models and in vitro functional assays. mice with a megakaryocyte-specific Gfi1b deletion exhibit macrothrombocytopenia, megakaryocytic dysplasia and platelet defect reminiscent of GFI1B-related thrombocytopenia (PMIDs: 28082345, 11825872, 30894540). GFI1B is a transcription repressor and in HEK293T cells transfected with the wild-type GFI1B or mutant GFI1B the wild type GFI1B repressed expression of the reporter gene while the mutant was unable to repress this expression (PMID 27122003). Megakaryocytes differentiated from patients-derive iPSCs recapitulates the megakaryocyte defect of Platelet-type bleeding disorder-17 (PMID 28880435). In summary, GFI1B is definitively associated with Platelet-type bleeding disorder-17. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0008495
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015372
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals have increased bleeding tendency (of variable severity), and awareness may allow preventive measures and early management of bleeding complications
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GFI1B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001377304.1. 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 | 13 | 14 | |||
| missense | 4 | 4 | 78 | 12 | 4 | 102 |
| nonsense | 2 | 1 | 1 | 4 | ||
| start loss | 0 | |||||
| frameshift | 2 | 1 | 3 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 9 | 5 | 81 | 25 | 4 | 124 |
Highest pathogenic variant AF is 0.00022869935
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001364233.1 | 6 | MANE Select | |
| Ensembl | ENSP00000361195.1 | 6 | MANE Select | |
| RefSeq | NP_001128503.1 | 5 | Standard | |
| RefSeq | NP_001358837.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gfi1b | Danio rerio | Structure: erythroid lineage cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- negative regulation of transcription by RNA polymerase II
- chromatin organization
- transcription by RNA polymerase II
- multicellular organism development
- cell population proliferation
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II transcription factor binding
- DNA binding
- protein binding
- metal ion binding
Cellular Component
- nucleus
- transcription factor complex
- nuclear matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000339463
- Coding exons
- 6
- Length
- 46152
- Individuals with no LoFs
- 125705
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 33
- Defined
- 125738
- p
- 0.000131
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.496 | 192 | 212 | 0.904 | 0.0000145 | 2171 |
| Missense (PolyPhen) | 65 | 89.955 | 0.72259 | 846 | ||
| Synonymous | -0.686 | 97 | 88.8 | 1.09 | 0.00000616 | 640 |
| Loss of Function | 1.97 | 8 | 16.7 | 0.479 | 9.89e-7 | 162 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000088 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0012 | 0.0011 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Essential proto-oncogenic transcriptional regulator necessary for development and differentiation of erythroid and megakaryocytic lineages. Component of a RCOR-GFI-KDM1A-HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation. Transcriptional repressor or activator depending on both promoter and cell type context; represses promoter activity of SOCS1 and SOCS3 and thus, may regulate cytokine signaling pathways. Cooperates with GATA1 to repress target gene transcription, such as the apoptosis regulator BCL2L1; GFI1B silencing in leukemic cell lines markedly increase apoptosis rate. Inhibits down- regulation of MYC and MYB as well as the cyclin-dependent kinase inhibitor CDKN1A/P21WAF1 in IL6-treated myelomonocytic cells. Represses expression of GATA3 in T-cell lymphomas and inhibits GATA1-mediated transcription; as GATA1 also mediates erythroid GFI1B transcription, both GATA1 and GFI1B participate in a feedback regulatory pathway controlling the expression of GFI1B gene in erythroid cells. Suppresses GATA1-mediated stimulation of GFI1B promoter through protein interaction. Binds to gamma- satellite DNA and to its own promoter, auto-repressing its own expression. Alters histone methylation by recruiting histone methyltransferase to target genes promoters. Plays a role in heterochromatin formation. {ECO:0000269|PubMed:12351384, ECO:0000269|PubMed:16177182, ECO:0000269|PubMed:16688220, ECO:0000269|PubMed:16782810, ECO:0000269|PubMed:17156408, ECO:0000269|PubMed:17272506, ECO:0000269|PubMed:17420275}.;
- Disease
- DISEASE: Bleeding disorder, platelet-type 17 (BDPLT17) [MIM:187900]: An autosomal dominant disorder characterized by increased bleeding tendency due to platelet dysfunction, and associated with macrothrombocytopenia and red cell anisopoikilocytosis. Platelets appear abnormal on light microscopy, while electron microscopy shows a heterogeneous decrease of alpha granules within platelets. Bone marrow biopsy shows increased numbers of abnormal megakaryocytes, suggesting a defect in megakaryopoiesis and platelet production. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other exhibit only abnormal bleeding with surgery. {ECO:0000269|PubMed:23927492, ECO:0000269|PubMed:24325358}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.158
Intolerance Scores
- LoFtool
- 0.626
- RVIS EVS
- 0.22
- RVIS percentile EVS
- 68.38
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.872
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |