GeneBe

TCF12

protein-coding

transcription factor 12, the group of Basic helix-loop-helix proteins

Gene summary

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]

MANE transcript

NM_207037.2

Inheritance

AR, AD

ClinVar variants

P:142U:249B:47

Top phenotype

Hypogonadotropic hypogonadism 26 with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr15:56,918,623-57,299,281

External References & Databases

Ensembl (ENSG00000140262)NCBI Gene (6938)OMIM (600480)HGNC:11623GenCCUniProt (Q99081)AlphaFoldClinVar (TCF12)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~380.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kallmann syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018800

Submitter: Franklin by Genoox

13 families with an anosmic form of IGD (Kallmann syndrome) were found to carry loss-of-function mutations in TCF12 gene.

TCF12-related craniosynostosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014128

Submitter: G2P

hypogonadotropic hypogonadism 26 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030534

Submitter: Labcorp Genetics (formerly Invitae)

Kallmann syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Franklin by Genoox

13 families with an anosmic form of IGD (Kallmann syndrome) were found to carry loss-of-function mutations in TCF12 gene.

TCF12-related craniosynostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014128

Submitter: Genomics England PanelApp

hypogonadotropic hypogonadism 26 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030534

Submitter: PanelApp Australia

isolated brachycephalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018114

Submitter: Orphanet

TCF12-related craniosynostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014128

Submitter: Labcorp Genetics (formerly Invitae)

TCF12-related craniosynostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014128

Submitter: PanelApp Australia

TCF12-related craniosynostosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014128

Submitter: ClinGen

TCF12 was first reported in relation to autosomal dominant TCF12-related craniosynostosis in 2013 (Sharma et al., PMID: 23354436). TCF12-related craniosynostosis most often involve the fusion of coronal sutures and individuals can present with other syndromic features including dental malocclusion, blepharoptosis, dysmorphic appearance of the face and external ears, and minor limb anomalies (PMID: 23354436). Eleven variants (frameshift, nonsense, splice) that have been reported in 11 probands in 4 publications (PMIDs: 23354436, 25271085, 24736737, 30858722) are included in this curation. More evidence is available in the literature but the maximum points for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be haploinsufficiency (heterozygous loss of function). This gene-disease association is also supported by animal models, expression studies, and protein interaction with TWIST1 (PMIDs: 23354436, 30375332, 32179550). In summary, there is definitive evidence to support the relationship between TCF12 and autosomal dominant TCF12-related craniosynostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 1/28/21 (SOP Version 8).

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 26 with or without anosmiaAD

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease

Refs: 23354436Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCF12 variants in ClinVar

18 Conditions Cataloged
not providedTotal: 328
Inborn genetic diseasesTotal: 103
TCF12-related craniosynostosisTotal: 66
TCF12-related disorderTotal: 21
not specifiedTotal: 18
Hypogonadotropic hypogonadism 26 with or without anosmiaTotal: 13
HYPOGONADOTROPIC HYPOGONADISM 26 WITH ANOSMIATotal: 5
Craniosynostosis syndromeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_207037.2. 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
4
clinvar
24
clinvar
5
clinvar
 33
missense
5
clinvar
5
clinvar
230
clinvar
17
clinvar
1
clinvar
 258
nonsense
33
clinvar
11
clinvar
2
clinvar
 46
start loss
0
frameshift
48
clinvar
20
clinvar
7
clinvar
 75
splice donor/acceptor (+/-2bp)
6
clinvar
14
clinvar
6
clinvar
 26
Total9250249416438

Highest pathogenic variant AF is 0.0000027361914

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 126 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_207037.2RefSeqNP_996920.119MANE Select
ENST00000333725.10EnsemblENSP00000331057.619MANE Select
NM_001306219.3RefSeqNP_001293148.113Standard
NM_001306220.3RefSeqNP_001293149.111Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Developmental Biology
  • Gene expression (Transcription)
  • Generic Transcription Pathway
  • RNA Polymerase II Transcription
  • CDO in myogenesis

Biological Process

  • regulation of transcription by RNA polymerase II
  • immune response
  • muscle organ development
  • positive regulation of neuron differentiation
  • 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
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA-binding transcription factor activity
  • protein binding

Cellular Component

  • nuclear chromatin
  • nucleus
  • nucleoplasm
  • transcription factor complex
  • cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000438423
Coding exons
19
Length
380659
Individuals with no LoFs
125728
Homozygous LoFs
0
Heterozygous LoFs
20
Defined
125748
p
0.0000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8903383870.8730.00001954593
Missense (PolyPhen)107179.870.594872061
Synonymous-1.401581371.150.000006951385
Loss of Function4.58838.80.2060.00000199474

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000160.00016rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000790.000079rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcriptional regulator. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3').;
Disease
DISEASE: Craniosynostosis 3 (CRS3) [MIM:615314]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:23354436, ECO:0000269|PubMed:25271085}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.190

Intolerance Scores

LoFtool
0.622
RVIS EVS
-0.71
RVIS percentile EVS
14.67

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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