TCF4

Chr 18

transcription factor 4

Also known as: CDG2T, E2-2, FCD2, FECD3, ITF-2, ITF2, PTHS, SEF-2

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]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtPitt-Hopkins syndrome
UniProtCorneal dystrophy, Fuchs endothelial, 3

Clinical highlights

Gene-disease validity (ClinGen)
Pitt-Hopkins syndrome · ADDefinitivesufficient evidence for diagnostic panels
Interpreting a novel variant
Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.
4
Active trials
214
Pubs (1 yr)
P/LP submissions
P/LP missense
0.22
LOEUF· LoF intol.
LOF
Mechanism· G2P
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GeneReview available — TCF4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint?
0.22LOEUF
pLI 1.000
Z-score 5.44
OE 0.09 (0.050.22)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?
4.10Z-score
OE missense 0.44 (0.390.50)
187 obs / 425.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?
LoF OE?0.09 (0.050.22)
00.351.4
Missense OE?0.44 (0.390.50)
00.61.4
Synonymous OE?0.97
01.21.6
LoF obs/exp: 4 / 42.1Missense obs/exp: 187 / 425.1Syn Z: 0.28

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

TCF4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

VCEP specificationsRett/Angelman-like DisordersPilot
Specifications ↗Panel ↗