GeneBe

TCF4

protein-coding

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

Gene summary

This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

MANE transcript

NM_001083962.2

Inheritance

AD

ClinVar variants

P:294U:327B:245

Top phenotype

Corneal dystrophy, Fuchs endothelial, 3; Pitt-Hopkins syndrome

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr18:55,222,185-55,664,787

External References & Databases

Ensembl (ENSG00000196628)NCBI Gene (6925)OMIM (602272)HGNC:11634GenCCUniProt (P15884)AlphaFoldClinVar (TCF4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~442.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Pitt-Hopkins syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012589

Submitter: ClinGen

Loss-of-function variants of the TCF4 gene cause the rare intellectual disability known as Pitt-Hopkins syndrome (PHS). PHS is characterized by specific dysmorphic facial features, periodic hyperventilation, early-onset seizures, microcephaly, and severe developmental delay. Sequence variants causing a loss of function include nonsense, frameshift, splice, and missense variants, and deletions affecting the TCF4 gene have also been reported. Phenotype is generally independent of variant type. TCF4 is a transcription factor believed to regulate central nervous system development. Mouse models of TCF4 haploinsufficiency support the neurological phenotypes of PHS (Zhuang 1996, Flora 2007, Kennedy 2016, Thaxton 2018). In summary, TCF4 is definitively associated with PHS in an autosomal dominant manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK100240/)

Fuchs' endothelial dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005321

Submitter: Orphanet

Pitt-Hopkins syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012589

Submitter: Labcorp Genetics (formerly Invitae)

corneal dystrophy, Fuchs endothelial, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013203

Submitter: G2P

Pitt-Hopkins syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012589

Submitter: Orphanet

autism spectrum disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Ambry Genetics

intellectual disabilityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

Pitt-Hopkins syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012589

Submitter: G2P

Pitt-Hopkins syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012589

Submitter: Ambry Genetics

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

Pitt-Hopkins syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012589

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Corneal dystrophy, Fuchs endothelial, 3; Pitt-Hopkins syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: 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

Refs: 728011; 17436254; 17478476; 17436255; 18728071; 19235238; 19938247; 22045651; 24255041; 25593321; 25722209Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCF4 variants in ClinVar

31 Conditions Cataloged
Pitt-Hopkins syndromeTotal: 800
not providedTotal: 337
not specifiedTotal: 126
Inborn genetic diseasesTotal: 122
TCF4-related disorderTotal: 60
Corneal dystrophy, Fuchs endothelial, 3Total: 24
Intellectual disabilityTotal: 6
Global developmental delayTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001083962.2. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
8
clinvar
170
clinvar
5
clinvar
 184
missense
21
clinvar
42
clinvar
309
clinvar
55
clinvar
15
clinvar
 442
nonsense
32
clinvar
11
clinvar
1
clinvar
 44
start loss
1
clinvar
 1
frameshift
95
clinvar
34
clinvar
5
clinvar
 134
splice donor/acceptor (+/-2bp)
31
clinvar
27
clinvar
3
clinvar
 61
Total18011432722520866

Highest pathogenic variant AF is 0.0000065727204

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 146 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001083962.2RefSeqNP_001077431.118MANE Select
ENST00000354452.8EnsemblENSP00000346440.318MANE Select
NM_001243226.3RefSeqNP_001230155.220Standard
NM_001243227.2RefSeqNP_001230156.117Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tcf4Danio rerio

Structure: post-vent region

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • WNT-Core
  • Neural Crest Differentiation
  • Corticotropin-releasing hormone signaling pathway
  • Mesodermal Commitment Pathway
  • TCF dependent signaling in response to WNT

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

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

Cellular Component

  • nuclear chromatin
  • nucleus
  • transcription factor complex
  • beta-catenin-TCF7L2 complex
  • beta-catenin-TCF complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000398339
Coding exons
20
Length
442457
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.101874250.4400.00002325060
Missense (PolyPhen)33138.220.238741593
Synonymous0.2761571610.9720.000009751507
Loss of Function5.44442.10.09500.00000223499

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec
0.296

Intolerance Scores

LoFtool
0.294
RVIS EVS
-0.56
RVIS percentile EVS
19.54

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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