TCF12

Chr 15ADAR

transcription factor 12

Also known as: CRS3, HEB, HH26, HTF4, HsT17266, TCF-12, bHLHb20, p64

NCBI Gene: 6938 ENSG00000140262 UniProt: Q99081 OMIM: 600480

The protein is a basic helix-loop-helix transcription factor that recognizes E-box DNA sequences and regulates lineage-specific gene expression through heterodimerization with other bHLH proteins. Loss-of-function mutations cause craniosynostosis 3 and hypogonadotropic hypogonadism with or without anosmia through both autosomal dominant and autosomal recessive inheritance patterns. The protein is expressed in multiple tissues including skeletal muscle, thymus, and immune cells where it controls developmental gene expression programs.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH) E-protein family that recognizes the consensus binding site (E-box) CANNTG. This encoded protein is expressed in many tissues, among them skeletal muscle, thymus, B- and T-cells, and may participate in regulating lineage-specific gene expression through the formation of heterodimers with other bHLH E-proteins. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Craniosynostosis 3MIM #615314

Hypogonadotropic hypogonadism 26 with or without anosmiaMIM #619718

ADAR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · TCF12-related craniosynostosis · AD · ClinGen 2021

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.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.37

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — TCF12

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.676

Z-score 4.58

OE 0.21 (0.12–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.89Z-score

OE missense 0.87 (0.80–0.95)

338 obs / 387.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.12–0.37)

0≤0.351.4

Missense OE?0.87 (0.80–0.95)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 8 / 38.8Missense obs/exp: 338 / 387.3Syn Z: -1.40

Background carrier burden — how many people carry a rare variant somewhere in TCF12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 73

1,028 rare PASS variants

Rare truncating (LoF)

1 in 1,700

125 rare PASS variants

Rare synonymous (reference)

1 in 200

347 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TCF12. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 87	1 in 2,400
South Asian	~43k	1 in 84	1 in 510
Remaining (unassigned)	~30k	1 in 100	1 in 2,100
European (Finnish)	~27k	1 in 240	1 in 2,200
Admixed American	~22k	1 in 77	1 in 1,300
African / African American	~21k	1 in 75	1 in 1,200
East Asian	~20k	1 in 65	1 in 1,800
Ashkenazi Jewish	~13k	1 in 250	1 in 1,500
Middle Eastern	~2,884	1 in 60	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 19 coding exons well covered in gnomAD exomes and genomes.? see exons ↓