TCF4

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

Basic information

Region (hg38): 18:55222184-55664787

Links

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

Phenotypes

GenCC

Source: genCC

• 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: 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 (737 variants)
• not provided (295 variants)
• not specified (85 variants)
• Inborn genetic diseases (72 variants)
• TCF4-related condition (9 variants)
• Corneal dystrophy, Fuchs endothelial, 3 (7 variants)
• Pitt-Hopkins syndrome;Corneal dystrophy, Fuchs endothelial, 3 (5 variants)
• Intellectual disability (5 variants)
• Corneal dystrophy, Fuchs endothelial, 3;Pitt-Hopkins syndrome (3 variants)
• See cases (3 variants)
• Global developmental delay (2 variants)
• Hereditary spastic paraplegia 4 (1 variants)
• 7 conditions (1 variants)
• Esophageal atresia;Pyloric stenosis (1 variants)
• Developmental disorder (1 variants)
• Neurodevelopmental disorder (1 variants)
• Microcephaly (1 variants)
• Autism spectrum disorder (1 variants)
• Oculomotor apraxia (1 variants)
• Cerebral hypoplasia;Global developmental delay (1 variants)
• SUDDEN INFANT DEATH SYNDROME (1 variants)
• Severe intellectual deficiency (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.

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			4	134	5	143
missense	13	27	205	28	12	285
nonsense	27	6	1			34
start loss						0
frameshift	63	20	2			85
inframe indel	1	4	5			10
splice donor/acceptor (+/-2bp)	23	18	5			46
splice region	2	3	17	24	3	49
non coding	1	1	97	119	91	309
Total	128	76	319	281	108

Variants in TCF4

This is a list of pathogenic ClinVar variants found in the TCF4 region.

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

Position	Type	Phenotype	Significance	ClinVar
18-55222481-GA-G		Pitt-Hopkins syndrome	Uncertain significance (Jun 14, 2016)
18-55222481-G-GA		Pitt-Hopkins syndrome	Benign (Jun 14, 2016)
18-55222532-A-G		Pitt-Hopkins syndrome	Benign (Jan 13, 2018)
18-55222555-C-T		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55222556-C-T		Pitt-Hopkins syndrome	Uncertain significance (Jan 12, 2018)
18-55222578-A-C		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55222617-A-G		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55222624-C-T		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55222641-TTC-T		Pitt-Hopkins syndrome	Uncertain significance (Jun 14, 2016)
18-55222652-A-G		Pitt-Hopkins syndrome	Uncertain significance (Jan 12, 2018)
18-55222665-C-T		Pitt-Hopkins syndrome	Uncertain significance (Jan 12, 2018)
18-55222666-G-A		Pitt-Hopkins syndrome	Benign (Jan 12, 2018)
18-55222696-T-C		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55222716-T-C		Pitt-Hopkins syndrome	Uncertain significance (Jan 12, 2018)
18-55222736-T-C		Pitt-Hopkins syndrome	Benign (Jan 13, 2018)
18-55222795-A-G		Pitt-Hopkins syndrome	Uncertain significance (Jan 12, 2018)
18-55222842-CGTCA-C		Pitt-Hopkins syndrome	Likely benign (Jun 14, 2016)
18-55222911-C-A		Pitt-Hopkins syndrome	Uncertain significance (Jan 12, 2018)
18-55222929-A-G		Pitt-Hopkins syndrome	Benign (Jan 12, 2018)
18-55223016-A-G		Pitt-Hopkins syndrome	Benign (Jan 12, 2018)
18-55223128-C-G		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55223202-T-C		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55223246-C-T		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55223283-T-C		Pitt-Hopkins syndrome	Uncertain significance (Jan 13, 2018)
18-55223412-T-A		Pitt-Hopkins syndrome	Uncertain significance (Apr 27, 2017)

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
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: 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

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