TCF3
protein-codingtranscription factor 3, the group of Basic helix-loop-helix proteins
Gene summary
This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development. Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1), childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Sep 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~43.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: SD
Disease ID:MONDO:0011096
Submitter: ClinGen
*TCF3* was first reported in relation to autosomal agammaglobulinemia in 2013 ( PMID: 24216514). *TCF3* encodes the 2 broadly expressed founding members of the basic helix-loop-helix (bHLH) family of transcription factors, E12 and E47. They are identical except for their bHLH domains, which are provided by alternatively spliced exons. E12 and E47 are essential in the differentiation process of common lymphoid progenitors into B-lineage cells and are key regulators of B-cell development. Both autosomal dominant and autosomal recessive inheritance have been reported. Due to lack of distinctive features in the small number of patients reported and the experimental evidence that supports autosomal recessive and autosomal dominant disease, the antibody deficiency GCEP came to the decision of lumping both modes of inheritance at this stage. A de-novo mutation that results in a dominant negative effect, has been reported in 5 unrelated individuals in 2 publications (PMIDs: 24216514 and 33905048). A heterozygous frameshift has been detected in a proband with reduced switched memory cells and recurrent infections (PMID: 29114388). Biallelic TCF3 mutations (a large deletion and a nonsense) have been reported in 3 patients (PMIDs: 30063982 and Barbouche, et al., 2016) Experimental evidence includes expression in relevant tissues and animal model. B cells of E2A (-I-) mice are arrested at an early stage of B cell differentiation. Heterozygote animals also showed decreased numbers of both pro-B and mature B cells (PMID: 8001124). In summary *TCF3* is definitively associated with autosomal agammaglobulinemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Gene Clinical Validity Standard Operating Procedures (SOP) -SOP8
Inheritance Pattern: AR
Disease ID:MONDO:0014840
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0859234
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014840
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014840
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011096
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Individuals have been described with severe and recurrent infrections, and awareness may allow prompt diagnosis and early and aggressive treatment of infections; In recessive forms of disease, an individual with leukemia has been described, and awareness may allow early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TCF3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003200.5. 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 | 10 | 232 | 12 | 254 | ||
| missense | 485 | 31 | 2 | 518 | ||
| nonsense | 9 | 4 | 13 | |||
| start loss | 0 | |||||
| frameshift | 10 | 1 | 11 | |||
| splice donor/acceptor (+/-2bp) | 10 | 6 | 16 | |||
| Total | 19 | 11 | 505 | 263 | 14 | 812 |
Highest pathogenic variant AF is 0.0000052112428
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003191.1 | 18 | MANE Select | |
| Ensembl | ENSP00000262965.5 | 18 | MANE Select | |
| RefSeq | NP_001129611.1 | 18 | MANE Plus Clinical | |
| RefSeq | NP_001338707.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tcf3a | Danio rerio | Structure: somite Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HTLV-I infection - Homo sapiens (human)
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Transcriptional misregulation in cancer - Homo sapiens (human)
- WNT-Core
- Hair Follicle Development- Induction (Part 1 of 3)
Biological Process
- negative regulation of transcription by RNA polymerase II
- B cell lineage commitment
- transcription, DNA-templated
- regulation of transcription, DNA-templated
- B cell differentiation
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- transcription factor complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262965
- Coding exons
- 18
- Length
- 43314
- Individuals with no LoFs
- 125734
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125745
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.228 | 426 | 413 | 1.03 | 0.0000286 | 4065 |
| Missense (PolyPhen) | 142 | 144.66 | 0.98164 | 1388 | ||
| Synonymous | -2.40 | 233 | 191 | 1.22 | 0.0000157 | 1343 |
| Loss of Function | 3.72 | 9 | 31.5 | 0.285 | 0.00000165 | 362 |
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 | 0.00012 | 0.00011 | rare |
| Finnish | 0.000051 | 0.000046 | rare |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000034 | 0.000033 | rare |
| Other | 0.00020 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional regulator. Involved in the initiation of neuronal differentiation. Heterodimers between TCF3 and tissue- specific basic helix-loop-helix (bHLH) proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation. Dimers bind DNA on E- box motifs: 5'-CANNTG-3'. Binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer. Binds to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region. {ECO:0000250|UniProtKB:P15806}.;
- Disease
- DISEASE: Note=Chromosomal aberrations involving TCF3 are cause of forms of pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocation t(1;19)(q23;p13.3) with PBX1. TCF3-PBX1 transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members of the PBX protein family (PubMed:1967983, PubMed:1671560). Translocation t(17;19)(q22;p13.3) with HLF (PubMed:1386162). Inversion inv(19)(p13;q13) with TFPT (PubMed:10086727). {ECO:0000269|PubMed:10086727, ECO:0000269|PubMed:1386162, ECO:0000269|PubMed:1671560, ECO:0000269|PubMed:1967983}.; DISEASE: Agammaglobulinemia 8, autosomal dominant (AGM8) [MIM:616941]: A form of agammaglobulinemia, a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. {ECO:0000269|PubMed:24216514}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.494
Intolerance Scores
- LoFtool
- 0.497
- RVIS EVS
- -0.08
- RVIS percentile EVS
- 47.26
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- 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 |