SPI1
protein-codingSpi-1 proto-oncogene, the group of ETS transcription factor family
Gene summary
This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development. The nuclear protein binds to a purine-rich sequence known as the PU-box found near the promoters of target genes, and regulates their expression in coordination with other transcription factors and cofactors. The protein can also regulate alternative splicing of target genes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~54.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0030529
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0030529
Submitter: ClinGen
The relationship between *SPI1* and Agammaglobulinemia 10, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework. *SPI1* encodes an ETS-domain transcription factor (PU.1). PU.1 is a key transcriptional regulator required in the development of multiple hematopoietic lineages. The phenotype associated with agammaglobulinemia 10 due to *SPI1* variants is characterized by early childhood onset of recurrent viral and bacterial infections affecting various organ systems, sinopulmonary infections with encapsulated bacteria, absent or low B cells and hypo or agammaglobulinemia. (Le Coz et al, 2021; PMID: 33951726). SPI1 was first reported in relation to autosomal dominant agammaglobulinemia in 2021 (Le Coz et al, 2021; PMID: 33951726). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (10.5 points): There have been 8 unrelated patients from 3 publication with germline, heterozygous variants in *SPI1* (PMIDs: 33951726, 38500873, 39052144). The 7 variants reported included 2 frameshift variants, 3 nonsense variants and 2 missense variants. Segregation analysis performed on 4 of the individuals revealed that the variant was de novo in all 4 of these probands (PMID: 33951726). The mechanism of disease is expected to be haploinsufficiency. Functional studies in patient cells and in-vitro cultures of mutant-transfected cells suggest that the variant impacts include the decay mRNA transcripts, destabilization of the PU.1 protein, interferance with PU.1 nuclear localization and / or alteratrion of PU.1 ETS domain-DNA binding. (PMID: 33951726) Summary of experimental data (3 points): This gene-disease relationship is supported by its biochemical function (PMID: 15469848) and expression in B cells (PMID: 2180582), as well as both cell culture and mouse model evidence. Adoptive transfer of hematopoietic stem and progenitor cells (HSPCs) from a patient’s unaffected sibling normalised PU.1 expression and resolved B cell and cDC deficiencies (PMID: 33951726). A cell culture model using CRISPR/Cas9 to edit the SPI1 locus in human HSPCs showed that myeloid and B cells were not tolerant to frameshift edits (PMID: 33951726). Germline homozygous *SPI1* knock-out mice were embryonically lethal with testing of embryos showing elimination of B lineage progenitors (PMID: 8079170). Conditionally knocked out mice were found to partially recapitulate the cellular phenotype seen in humans demonstrating a deficiency of cDC cells (PMID: 30611612). In summary, there is definitive evidence supporting the relationship between *SPI1* and autosomal dominant Agammaglobulinemia 10. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Antibody Deficiencies GCEP on August, 16 2022. It was reevaluated on December 12, 2024. As a result of this reevaluation, the classification changed from Strong to Definitive due to the replication of this gene-disease relationship over time and two additional case reports (PMIDs: 38500873, 39052144). A recent analysis was performed of 134 *SPI1* variants in agammaglobulinemia patients, expanding the genotype-phenotype correlation of this disease (PMID: 39854693).
Inheritance Pattern: AD
Disease ID:MONDO:0030529
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: The condition may include early-onset, recurrent infections, and early diagnoses may enable management (eg, with IVIG and an altered vaccination regimen), and early and aggressive treatment of infections; HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SPI1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003120.3. 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 | 3 | 1 | 5 | ||
| missense | 4 | 3 | 33 | 94 | 134 | |
| nonsense | 7 | 1 | 1 | 9 | ||
| start loss | 0 | |||||
| frameshift | 8 | 2 | 10 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 20 | 4 | 37 | 3 | 95 | 159 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003111.2 | 5 | MANE Select | |
| Ensembl | ENSP00000367799.4 | 5 | MANE Select | |
| RefSeq | NP_001074016.1 | 5 | Standard | |
| Ensembl | ENSP00000227163.4 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| spi1b | Danio rerio | Structure: neutrophil Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Acute myeloid leukemia - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Transcriptional misregulation in cancer - Homo sapiens (human)
- Osteoclast differentiation - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- lymphoid progenitor cell differentiation
- regulation of transcription by RNA polymerase II
- lymphocyte differentiation
- 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
- RNA polymerase II transcription factor binding
- DNA-binding transcription repressor activity, RNA polymerase II-specific
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000227163
- Coding exons
- 5
- Length
- 23717
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.35 | 75 | 158 | 0.474 | 0.00000882 | 1782 |
| Missense (PolyPhen) | 16 | 61.851 | 0.25868 | 678 | ||
| Synonymous | -0.219 | 75 | 72.6 | 1.03 | 0.00000474 | 496 |
| Loss of Function | 3.24 | 0 | 12.3 | 0.00 | 5.24e-7 | 145 |
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 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds to the PU-box, a purine-rich DNA sequence (5'- GAGGAA-3') that can act as a lymphoid-specific enhancer. This protein is a transcriptional activator that may be specifically involved in the differentiation or activation of macrophages or B- cells. Also binds RNA and may modulate pre-mRNA splicing (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.668
Intolerance Scores
- LoFtool
- 0.464
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.25
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |