GFI1
protein-codinggrowth factor independent 1 transcriptional repressor, the group of SNAG transcriptional repressors|Zinc fingers C2H2-type
Gene summary
This gene encodes a nuclear zinc finger protein that functions as a transcriptional repressor. This protein plays a role in diverse developmental contexts, including hematopoiesis and oncogenesis. It functions as part of a complex along with other cofactors to control histone modifications that lead to silencing of the target gene promoters. Mutations in this gene cause autosomal dominant severe congenital neutropenia, and also dominant nonimmune chronic idiopathic neutropenia of adults, which are heterogeneous hematopoietic disorders that cause predispositions to leukemias and infections. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]
- ZNF163
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013139
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008742
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018542
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0013139
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013139
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; The condition may predispose to leukemia, and thus surveillance for hematologic anomalies may allow early diagnosis and treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GFI1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005263.5. 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 | 282 | 1 | 283 | |||
| missense | 1 | 492 | 21 | 514 | ||
| nonsense | 5 | 5 | ||||
| start loss | 0 | |||||
| frameshift | 5 | 5 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 0 | 503 | 303 | 1 | 808 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005254.2 | 6 | MANE Select | |
| Ensembl | ENSP00000294702.5 | 6 | MANE Select | |
| RefSeq | NP_001120687.1 | 6 | Standard | |
| RefSeq | NP_001120688.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gfi1aa | Danio rerio | Structure: myeloid lineage restricted progenitor cell Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Development and heterogeneity of the ILC family
- Validated targets of C-MYC transcriptional repression
Biological Process
- regulation of transcription involved in G1/S transition of mitotic cell cycle
- negative regulation of transcription by RNA polymerase II
- negative regulation of calcidiol 1-monooxygenase activity
- negative regulation of vitamin D biosynthetic process
- negative regulation of neuron projection development
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- protein binding
- transcription regulatory region DNA binding
Cellular Component
- nucleus
- nucleoplasm
- nuclear matrix
- nuclear body
- transcriptional repressor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000370332
- Coding exons
- 6
- Length
- 12115
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125747
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.59 | 177 | 247 | 0.716 | 0.0000132 | 2670 |
| Missense (PolyPhen) | 37 | 90.726 | 0.40782 | 992 | ||
| Synonymous | 2.53 | 78 | 112 | 0.696 | 0.00000612 | 859 |
| Loss of Function | 2.83 | 4 | 16.3 | 0.245 | 7.04e-7 | 195 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000037 | 0.000035 | rare |
| South Asian | 0.00011 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription repressor essential for hematopoiesis. Functions in a cell-context and development-specific manner. Binds to 5'-TAAATCAC[AT]GCA-3' in the promoter region of a large number of genes. Component of several complexes, including the EHMT2- GFI1-HDAC1, AJUBA-GFI1-HDAC1 and RCOR-GFI-KDM1A-HDAC complexes, that suppress, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Regulates neutrophil differentiation, promotes proliferation of lymphoid cells, and is required for granulocyte development. Mediates, together with U2AF1L4, the alternative splicing of CD45 and controls T-cell receptor signaling. Regulates the endotoxin- mediated Toll-like receptor (TLR) inflammatory response by antagonizing RELA. Cooperates with CBFA2T2 to regulate ITGB1- dependent neurite growth. Controls cell-cycle progression by repressing CDKNIA/p21 transcription in response to TGFB1 via recruitment of GFI1 by ZBTB17 to the CDKNIA/p21 and CDKNIB promoters. Required for the maintenance of inner ear hair cells. {ECO:0000269|PubMed:11060035, ECO:0000269|PubMed:12778173, ECO:0000269|PubMed:16287849, ECO:0000269|PubMed:17197705, ECO:0000269|PubMed:17646546, ECO:0000269|PubMed:18805794, ECO:0000269|PubMed:19026687, ECO:0000269|PubMed:19164764, ECO:0000269|PubMed:20190815, ECO:0000269|PubMed:20547752, ECO:0000269|PubMed:8754800}.;
- Disease
- DISEASE: Neutropenia, severe congenital 2, autosomal dominant (SCN2) [MIM:613107]: A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. {ECO:0000269|PubMed:12778173}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dominant nonimmune chronic idiopathic neutropenia of adults (NI-CINA) [MIM:607847]: Relatively mild form of neutropenia diagnosed in adults, but predisposing to leukemia in a subset of patients. {ECO:0000269|PubMed:12778173}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.288
Intolerance Scores
- LoFtool
- 0.557
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.27
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.994
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |