TCF4

transcription factor 4, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 18:55222185-55664787

Links

ENSG00000196628 ∙ NCBI:6925 ∙ OMIM:602272 ∙ HGNC:11634 ∙ Uniprot:P15884 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability (Limited), mode of inheritance: AD
• Pitt-Hopkins syndrome (Definitive), mode of inheritance: AD
• autism spectrum disorder (Limited), mode of inheritance: AD
• Pitt-Hopkins syndrome (Definitive), mode of inheritance: AD
• Pitt-Hopkins syndrome (Strong), mode of inheritance: AD
• Pitt-Hopkins syndrome (Supportive), mode of inheritance: AD
• Fuchs' endothelial dystrophy (Supportive), mode of inheritance: AD
• autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
• Pitt-Hopkins syndrome (Strong), mode of inheritance: AD
• Pitt-Hopkins syndrome (Definitive), mode of inheritance: AD
• corneal dystrophy, Fuchs endothelial, 3 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Corneal dystrophy, Fuchs endothelial, 3; Pitt-Hopkins syndrome	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic	728011; 17436254; 17478476; 17436255; 18728071; 19235238; 19938247; 22045651; 24255041; 25593321; 25722209

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TCF4 gene.

• Pitt-Hopkins_syndrome (778 variants)
• not_provided (304 variants)
• Inborn_genetic_diseases (106 variants)
• not_specified (92 variants)
• TCF4-related_disorder (29 variants)
• Corneal_dystrophy,_Fuchs_endothelial,_3 (22 variants)
• Intellectual_disability (6 variants)
• Global_developmental_delay (4 variants)
• Microcephaly (3 variants)
• See_cases (3 variants)
• Stereotypic_movement_disorder (1 variants)
• Hereditary_spastic_paraplegia_4 (1 variants)
• Autism_spectrum_disorder (1 variants)
• Feeding_difficulties_in_infancy (1 variants)
• Drooling (1 variants)
• Epicanthus (1 variants)
• Severe_intellectual_deficiency (1 variants)
• Cerebral_hypoplasia (1 variants)
• Oculomotor_apraxia (1 variants)
• Seizure (1 variants)
• Pyloric_stenosis (1 variants)
• Neurodevelopmental_disorder (1 variants)
• Anteverted_nares (1 variants)
• Esophageal_atresia (1 variants)
• Short_nose (1 variants)
• Congenital_myopathy (1 variants)
• SUDDEN_INFANT_DEATH_SYNDROME (1 variants)
• Developmental_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TCF4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001083962.2. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2		7	167	4	180
missense	21	42	289	52	14	418
nonsense	31	8	1			40
start loss			1			1
frameshift	93	30	3			126
splice donor/acceptor (+/-2bp)	27	26	4			57
Total	174	106	305	219	18

Highest pathogenic variant AF is 0.0000065727204

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TCF4	protein_coding	protein_coding	ENST00000398339	20	442457

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.10	187	425	0.440	0.0000232	5060
Missense in Polyphen		33	138.22	0.23874		1593
Synonymous	0.276	157	161	0.972	0.00000975	1507
Loss of Function	5.44	4	42.1	0.0950	0.00000223	499

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3'). Binds to the E-box present in the somatostatin receptor 2 initiator element (SSTR2-INR) to activate transcription (By similarity). Preferentially binds to either 5'-ACANNTGT-3' or 5'-CCANNTGG-3'. {ECO:0000250}.
• Disease: DISEASE: Pitt-Hopkins syndrome (PTHS) [MIM:610954]: A syndrome characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea. Features include intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, severe motor developmental delay, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. {ECO:0000269|PubMed:17436254, ECO:0000269|PubMed:17436255, ECO:0000269|PubMed:18728071, ECO:0000269|PubMed:19235238, ECO:0000269|PubMed:20184619, ECO:0000269|PubMed:22045651, ECO:0000269|PubMed:22777675, ECO:0000269|PubMed:25356899}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Corneal dystrophy, Fuchs endothelial, 3 (FECD3) [MIM:613267]: A late-onset form of Fuchs endothelial corneal dystrophy, a disease caused by loss of endothelium of the central cornea. It is characterized by focal wart-like guttata that arise from Descemet membrane and develop in the central cornea, epithelial blisters, reduced vision and pain. Descemet membrane is thickened by abnormal collagenous deposition. {ECO:0000269|PubMed:24255041, ECO:0000269|PubMed:25168903, ECO:0000269|PubMed:25593321}. Note=The disease is caused by mutations affecting the gene represented in this entry. Causative mutations are heterozygous TCF4 intronic trinucleotide repeat expansions (CTG)n. {ECO:0000269|PubMed:24255041, ECO:0000269|PubMed:25168903, ECO:0000269|PubMed:25593321}.; DISEASE: Note=Defects in TCF4 may cause autosomal dominant symmetrical acral keratoderma (SAK)syndrome. Symmetrical acral keratodermadefines is characterized by brown/black hyperkeratotic patches symmetrically distributed on the acral regions, especially the wrists, ankles, dorsa of hands, fingers and feet affects young and middle aged men. Patients have epidermis thickened by acanthosis and compact stratum corneum(PubMed:28921696). {ECO:0000269|PubMed:28921696}.
• Pathway: WNT-Core;Neural Crest Differentiation;Corticotropin-releasing hormone signaling pathway;Mesodermal Commitment Pathway;TCF dependent signaling in response to WNT;Wnt Signaling Pathway;Regulation of Wnt-B-catenin Signaling by Small Molecule Compounds;Development of pulmonary dendritic cells and macrophage subsets;Developmental Biology;Signaling by WNT;Signal Transduction;AndrogenReceptor;CDO in myogenesis;Myogenesis;Coregulation of Androgen receptor activity;Gastrin;Wnt;Regulation of nuclear beta catenin signaling and target gene transcription;Formation of the beta-catenin:TCF transactivating complex;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.296

Intolerance Scores

• loftool: 0.294
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.54

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

Zebrafish Information Network

• Gene name: tcf4
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: curved

Gene ontology

• Biological process: DNA-templated transcription, initiation;transcription initiation from RNA polymerase II promoter;positive regulation of neuron differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;protein-DNA complex assembly
• Cellular component: nuclear chromatin;nucleus;transcription factor complex;beta-catenin-TCF7L2 complex;beta-catenin-TCF complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;TFIIB-class transcription factor binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;protein binding;protein C-terminus binding;identical protein binding;protein homodimerization activity;bHLH transcription factor binding;protein heterodimerization activity;E-box binding