TCF4
transcription factor 4, the group of Basic helix-loop-helix proteins
Basic information
Region (hg38): 18:55222185-55664787
Links
Phenotypes
GenCC
Source:
- 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
- intellectual disability (Limited), mode of inheritance: AD
- Pitt-Hopkins syndrome (Definitive), mode of inheritance: AD
- autism spectrum disorder (Limited), mode of inheritance: AD
- corneal dystrophy, Fuchs endothelial, 3 (Strong), mode of inheritance: AD
- Pitt-Hopkins syndrome (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| 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
- Pitt-Hopkins_syndrome (750 variants)
- not_provided (293 variants)
- Inborn_genetic_diseases (102 variants)
- not_specified (91 variants)
- TCF4-related_disorder (29 variants)
- Corneal_dystrophy,_Fuchs_endothelial,_3 (21 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 | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 163 | 175 | ||||
| missense | 21 | 39 | 272 | 51 | 14 | 397 |
| nonsense | 30 | 38 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 93 | 30 | 125 | |||
| splice donor/acceptor (+/-2bp) | 27 | 23 | 55 | |||
| Total | 173 | 100 | 286 | 214 | 18 |
Highest pathogenic variant AF is 0.00000657272
Loading clinvar variants...
GnomAD
Source:
| 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 |
|---|---|---|---|---|---|---|
| 1.00 | 0.000188 | 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:
- 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
Haploinsufficiency Scores
- pHI
- 0.971
- hipred
- Y
- hipred_score
- 0.831
- ghis
- 0.540
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
- Tcf4
- Phenotype
- growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; vision/eye 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); hematopoietic system phenotype; pigmentation phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; limbs/digits/tail 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);
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