• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
TCF12 (HGNC:11623) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
transcription factor 12
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
HEB, HTF4, HsT17266, bHLHb20, p64
%HI
2.07(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.68(Read more about gnomAD pLI score)
LOEUF
0.37(Read more about gnomAD LOEUF score)
Cytoband
15q21.3
Genomic Coordinates
GRCh37/hg19: chr15:57210288-57583508 NCBI Ensembl UCSC
GRCh38/hg38: chr15:56918090-57291310 NCBI Ensembl UCSC
MANE Select Transcript
NM_207037.2 ENST00000333725.10 (Read more about MANE Select)
Function
Transcriptional regulator. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3') (By similarity). May be involved in the functional network that regulates the development of the GnRH axis (PubMed:32620954). {ECO:0000250|UniProtKB:Q61286, ECO:0000269|PubMed:32620954}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-19497
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
08/16/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • TCF12-related craniosynostosis Monarch
HI Evidence:
  • PUBMED: 23354436
    Sharma et al. (2013) report 38 heterozygous TCF12 variants in 347 samples from unrelated individuals with coronal or multisuture (including coronal) craniosynostosis, including 14 nonsense, 15 frameshift, 7 splicing and 2 missense changes. The authors report that "in cases with frameshift or splice site mutations, analyses of mRNA extracted from various cell types demonstrated relative under-expression of the mutant compared to the wild-type allele, consistent with nonsense-mediated decay leading to haploinsufficiency." Of 36 families with additional family members available for testing, 14 TCF12 variants were found to be de novo, and 22 were found to be inherited. Of the 34 additional family members found to carry TCF12 variants, only 16 were considered affected, suggesting a high rate of non-penetrance (47%).
  • PUBMED: 25271085
    Paumard-Hernández et al. (2015) screened for variants in common craniosynostosis genes (FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1) in a cohort of 182 Spanish individuals with craniosynostosis, identifying variants in 113. The authors then screened for variants in TCF12 in the remaining 69 individual, identifying 5 variants (4 novel, 1 previously reported in Sharma et al. (2013)). The previously reported variant, p.Ser281*, was found to be de novo in the individual in this cohort. Of the remaining 4 variants, the authors report that 3 are "clearly pathogenic" and 1 is of "uncertain significance." The three "clearly pathogenic" variants are all predicted to result in premature truncation of the protein. A minigene assay was performed for one of the variants to determine its effects on splicing. The authors state: "The de novo splice site alteration, TCF12 variant c.826-2A4G, identified in proband 3, affects one of the two highly conserved splice site nucleotides in the intron 10 splice site acceptor. A minigene assay confirmed experimentally the predicted splicing effects of the TCF12 variant c.826-2A4G: the mutation had a dual effect on splicing, leading to exon 11 skipping and also generating an alternative transcript with the recognition of a cryptic acceptor site (c.826_827del), leading to the premature termination(p.Ser276-Leufs*61). In both events, the mutant transcripts are predicted to be non-functional as they either affect the activation domain 2 of TCF12 or result in a prematurely truncated protein, which may be degraded by nonsense mediated decay." In both families in which a TCF12 variant was known to be inherited, incomplete penetrance was observed. The authors note that the p.Leu507Arg variant classified as being of uncertain significance was "absent in 400 Spanish healthy controls but present in 11/2184 (MAF=0.005) European Americans in the EVS database. As the EVS population has not been excluded for craniosynostosis and incomplete penetrance is a common phenomenon, functional analysis will be required to definitely determine the pathogenicity of this variant."
  • PUBMED: 30858722
    Goumenos et al., (2019) reported two heterozygous frameshift variants, c.1119delC/p.T373Tfs*23 and c.1836dupA/p.R613Tfs*5 in individuals from two families presented with coronal synostosis. Variable expressivity in two individuals, mother and proband with the frameshift variants, c.1119delC/p.T373Tfs*23, was noticed.
  • PUBMED: 27158814
    Goos et al., (2016) reported intragenic exon deletions (of sizes 84.9, 8.6, and 5.4 kb with exon 7-18, exon 19 and exon 20 removed, respectively); a duplication of TCF12 exons 19 and 20 in TCF12 gene in different families with TCF12‐related craniosynostosis by WES and confirmed by PCRs and sanger sequencing. The pathogenic effect of this duplication was confirmed by cDNA analysis. Therefore, TCF12‐related craniosynostosis can also be caused by large intragenic rearrangements and that there is no indication of a genotype–phenotype correlation.
  • PUBMED: 24648389
    Several large deletions of 15q21.3 that include TCF12 in addition to other genes have been reported in patients with craniosynostosis. For example, Le Tanno et al. (2014) (PMID: 24648389) report a 33-month-old male with coronal craniosynostosis, developmental delay, and dysmorphic features, and a 3.64Mb de novo deletion of 15q21.3q22.2 in the context of a maternally inherited translocation between chromosomes 2 and 15 (t(2;15)(q21;q21.3). See also PMIDs 2368808, 18449934.
HI Evidence Comments:
As described above, putative loss of function variants in TCF12 have been reported in individuals with craniosynostosis. Of note, in 2020, Davis et al. (PMID: 32620954) reported 13 loss of function mutations, 7 frameshifts; 4 nonsense variants and 2 canonical splice site variants, in individuals with individuals with Kallmann syndrome (KS, isolated GnRH deficiency) from 13 unrelated families (12 autosomal dominant and one autosomal recessive) using WES. Individuals from one family with KS and p.Ser497Cysfs*12 also presented craniosynostosis; 3 additional pedigrees with KS and noted craniosynostosis were noted, the remaining families were all sporadic presentations of KS only. In summary, eleven of 12 KS males with TCF12 heterozygous LoF variants reported in this study displayed severe neonatal hypogonadism as evidenced by micropenis and bilateral cryptorchidism. The authors report that there is no clear phenotype–genotype correlation to differentiate molecularly between the two traits, craniosynostosis and KS. In both disorders, the proposed mode of action is haploinsufficiency. TCF12 dysfunction is physiologically relevant to GnRH (the gonadotropin-releasing hormone) axis development in humans. Loss-of-function mutations in TCF12, cause syndromic and non-syndromic craniosynostosis, as well as Kallmann syndrome, which is an allelic disorder of TCF12 haploinsufficiency, expanding the observed genetic overlap between disorders of cranial and GnRH axis development and begin to dissect the relationships between genes and their protein products that affect the formation and function of the GnRH axis.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000015.9) (NC_000015.10)