TCF12

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

Basic information

Region (hg38): 15:56918623-57299281

Links

ENSG00000140262 ∙ NCBI:6938 ∙ OMIM:600480 ∙ HGNC:11623 ∙ Uniprot:Q99081 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• TCF12-related craniosynostosis (Strong), mode of inheritance: AD
• Kallmann syndrome (Strong), mode of inheritance: AR
• Kallmann syndrome (Strong), mode of inheritance: AD
• TCF12-related craniosynostosis (Strong), mode of inheritance: AD
• isolated plagiocephaly (Supportive), mode of inheritance: AD
• isolated brachycephaly (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 26 with or without anosmia (Strong), mode of inheritance: AD
• TCF12-related craniosynostosis (Strong), mode of inheritance: AD
• TCF12-related craniosynostosis (Definitive), mode of inheritance: AD
• TCF12-related craniosynostosis (Definitive), mode of inheritance: AD
• hypogonadotropic hypogonadism 26 with or without anosmia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 26 with or without anosmia	AD	Endocrine	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	Craniofacial; Endocrine; Musculoskeletal; Neurologic	23354436

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TCF12 gene.

• not_provided (317 variants)
• Inborn_genetic_diseases (96 variants)
• TCF12-related_craniosynostosis (60 variants)
• TCF12-related_disorder (21 variants)
• not_specified (17 variants)
• Hypogonadotropic_hypogonadism_26_with_or_without_anosmia (13 variants)
• HYPOGONADOTROPIC_HYPOGONADISM_26_WITH_ANOSMIA (5 variants)
• Craniosynostosis_syndrome (3 variants)
• Male_infertility_with_azoospermia_or_oligozoospermia_due_to_single_gene_mutation (2 variants)
• Autism_spectrum_disorder (2 variants)
• Common_craniosynostosis_syndromes (1 variants)
• Global_developmental_delay (1 variants)
• Intellectual_disability (1 variants)
• Developmental_delay (1 variants)
• Delayed_speech_and_language_development (1 variants)
• Coronal_craniosynostosis (1 variants)
• Hypogonadism_with_anosmia (1 variants)
• Developmental_disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TCF12 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000207037.2. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	22	5	31
missense	5	5	222	17	1	250
nonsense	30	10	2			42
start loss						0
frameshift	46	19	7			72
splice donor/acceptor (+/-2bp)	6	13	5			24
Total	87	47	240	39	6

Highest pathogenic variant AF is 0.0000027361914

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TCF12	protein_coding	protein_coding	ENST00000438423	19	380659

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125728	0	20	125748	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.890	338	387	0.873	0.0000195	4593
Missense in Polyphen		107	179.87	0.59487		2061
Synonymous	-1.40	158	137	1.15	0.00000695	1385
Loss of Function	4.58	8	38.8	0.206	0.00000199	474

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000272	0.000271
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000164	0.000163
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000794	0.0000791
Middle Eastern	0.000164	0.000163
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: Developmental Biology;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;CDO in myogenesis;Myogenesis;RUNX1 regulates transcription of genes involved in differentiation of HSCs;Transcriptional regulation by RUNX1 (Consensus)

Recessive Scores

• pRec: 0.190

Intolerance Scores

• loftool: 0.622
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.67

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Gene ontology

• 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;regulation of hematopoietic stem cell differentiation
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;transcription factor complex;cytoplasm;nuclear speck;intracellular membrane-bounded organelle;RNA polymerase II transcription factor complex
• 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;transcription factor binding;enhancer binding;cAMP response element binding;protein homodimerization activity;bHLH transcription factor binding;transcription regulatory region DNA binding;SMAD binding;protein heterodimerization activity;E-box binding;HMG box domain binding