TCF3

transcription factor 3, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 19:1609290-1652615

Links

ENSG00000071564 ∙ NCBI:6929 ∙ OMIM:147141 ∙ HGNC:11633 ∙ Uniprot:P15923 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal agammaglobulinemia (Supportive), mode of inheritance: AD
• agammaglobulinemia 8, autosomal dominant (Strong), mode of inheritance: AR
• agammaglobulinemia 8, autosomal dominant (Strong), mode of inheritance: AD
• autosomal agammaglobulinemia (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Agammaglobulinemia 8A, autosomal dominant; Agammaglobulinemia 8B, autosomal recessive	AD/AR	Allergy/Immunology/Infectious; Oncologic	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	Allergy/Immunology/Infectious; Oncologic	24216514; 28532655; 30063982

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TCF3 gene.

• not provided (706 variants)
• Inborn genetic diseases (30 variants)
• Agammaglobulinemia 8, autosomal dominant (22 variants)
• not specified (10 variants)
• TCF3-related condition (7 variants)
• Agammaglobulinemia 8, autosomal dominant;Agammaglobulinemia 8b, autosomal recessive (6 variants)
• Agammaglobulinemia 8b, autosomal recessive;Agammaglobulinemia 8, autosomal dominant (6 variants)
• Myeloproliferative neoplasm, unclassifiable (6 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TCF3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	177	18	198
missense	1		277	31	8	317
nonsense	4		1	1		6
start loss						0
frameshift	5	1				6
inframe indel			7	1		8
splice donor/acceptor (+/-2bp)		4				4
splice region			18	42	5	65
non coding			1	103	22	126
Total	10	5	289	313	48

Variants in TCF3

This is a list of pathogenic ClinVar variants found in the TCF3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-1611703-C-T		TCF3-related disorder	Likely benign (Sep 25, 2020)
19-1611710-C-T			Uncertain significance (Dec 18, 2022)
19-1611712-T-G			Uncertain significance (Oct 13, 2023)
19-1611714-T-G			Uncertain significance (Nov 10, 2022)
19-1611716-C-T			Likely benign (Oct 29, 2023)
19-1611718-C-T			Uncertain significance (Dec 07, 2022)
19-1611719-G-A			Likely benign (Aug 04, 2023)
19-1611721-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 24, 2023)
19-1611722-G-A			Likely benign (Dec 06, 2023)
19-1611724-G-A			Uncertain significance (Aug 03, 2023)
19-1611724-G-T		Agammaglobulinemia 8, autosomal dominant;Agammaglobulinemia 8b, autosomal recessive • Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 15, 2023)
19-1611727-T-G		TCF3-related disorder	Uncertain significance (Dec 30, 2022)
19-1611730-G-C			Uncertain significance (Oct 04, 2022)
19-1611732-G-C			Likely benign (Feb 14, 2023)
19-1611736-C-T			Uncertain significance (Dec 14, 2023)
19-1611737-G-A			Likely benign (Nov 23, 2022)
19-1611737-G-C			Uncertain significance (Dec 09, 2023)
19-1611739-T-G			Uncertain significance (Jul 19, 2022)
19-1611740-C-G			Benign (Dec 11, 2023)
19-1611742-G-A			Likely benign (May 02, 2023)
19-1611746-T-A			Likely benign (Nov 19, 2023)
19-1611746-T-C			Likely benign (Oct 05, 2023)
19-1611747-G-C			Uncertain significance (Dec 22, 2023)
19-1611748-G-C			Uncertain significance (Nov 07, 2022)
19-1611753-G-A			Uncertain significance (Jul 12, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TCF3	protein_coding	protein_coding	ENST00000262965	18	43314

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0258	0.974	125734	0	11	125745	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.228	426	413	1.03	0.0000286	4065
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.000117	0.000109
Finnish	0.0000509	0.0000462
European (Non-Finnish)	0.0000447	0.0000439
Middle Eastern	0.000117	0.000109
South Asian	0.0000344	0.0000327
Other	0.000200	0.000163

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Ectoderm Differentiation;Wnt Signaling Pathway;Wnt-beta-catenin Signaling Pathway in Leukemia;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Developmental Biology;Notch;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;CDO in myogenesis;Myogenesis;RUNX1 regulates transcription of genes involved in differentiation of HSCs;ID;Notch-mediated HES/HEY network;Transcriptional regulation by RUNX1;p38 signaling mediated by MAPKAP kinases;Regulation of nuclear SMAD2/3 signaling (Consensus)

Recessive Scores

• pRec: 0.494

Intolerance Scores

• loftool: 0.497
• rvis_EVS: -0.08
• rvis_percentile_EVS: 47.26

Haploinsufficiency Scores

• pHI: 0.853
• hipred: Y
• hipred_score: 0.704
• ghis: 0.635

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Tcf3
• Phenotype: reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; hematopoietic system phenotype; neoplasm; embryo phenotype; liver/biliary system phenotype; immune system phenotype; renal/urinary system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: tcf3a
• Affected structure: somite
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• 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;immunoglobulin V(D)J recombination;positive regulation of neuron differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of DNA-binding transcription factor activity;positive regulation of muscle cell differentiation;regulation of hematopoietic stem cell differentiation
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;transcription factor complex;cytoplasm;nuclear speck;RNA polymerase II transcription factor complex
• 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;transcription coactivator activity;protein binding;transcription factor binding;mitogen-activated protein kinase kinase kinase binding;enhancer binding;protein homodimerization activity;bHLH transcription factor binding;protein heterodimerization activity;repressing transcription factor binding;vitamin D response element binding;E-box binding