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

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 (35 variants)
• TCF12-related craniosynostosis (14 variants)
• Inborn genetic diseases (3 variants)
• HYPOGONADOTROPIC HYPOGONADISM 26 WITH ANOSMIA (1 variants)
• Craniosynostosis syndrome (1 variants)
• TCF12-related 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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	15	5	22
missense	1	3	93	10	1	108
nonsense	16	7				23
start loss						0
frameshift	26	11	5			42
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	8	2			11
splice region	2	3	6	3	1	15
non coding			3	44	41	88
Total	44	29	106	69	47

Highest pathogenic variant AF is 0.00000658

Variants in TCF12

This is a list of pathogenic ClinVar variants found in the TCF12 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-56919557-G-A			Likely benign (Apr 18, 2021)
15-56919764-G-A			Likely benign (May 20, 2019)
15-56919800-C-G			Likely benign (Jan 02, 2019)
15-56919924-A-T			Uncertain significance (Jan 26, 2022)
15-56919932-C-T			Uncertain significance (Dec 19, 2023)
15-56919932-C-CG		Hypogonadism with anosmia	Uncertain significance (Feb 02, 2022)
15-56919935-A-G		Inborn genetic diseases	Uncertain significance (Jun 18, 2024)
15-56919936-T-C			Uncertain significance (Feb 07, 2022)
15-56919970-C-T			Likely benign (May 21, 2018)
15-56919972-TA-T			Likely pathogenic (Nov 06, 2018)
15-56920007-G-C			Benign (Jul 18, 2023)
15-56920030-TTTTG-T			Likely benign (May 23, 2021)
15-56920275-G-A			Likely benign (Jan 18, 2020)
15-56920821-A-G			Benign (Oct 16, 2018)
15-56920981-T-C			Likely benign (Jan 02, 2019)
15-56921008-A-G		not specified	Benign (Jan 16, 2024)
15-56921030-T-A			Uncertain significance (Aug 27, 2023)
15-56921057-C-G		Inborn genetic diseases	Uncertain significance (Dec 30, 2023)
15-56921062-C-T			Uncertain significance (Oct 09, 2023)
15-56921080-A-G		Inborn genetic diseases	Uncertain significance (Mar 02, 2023)
15-56921085-A-G		not specified	Benign (Jan 15, 2024)
15-56921093-G-A			Uncertain significance (Feb 27, 2023)
15-56921373-G-A			Benign (Nov 08, 2018)
15-57063764-G-C		Inborn genetic diseases	Uncertain significance (May 01, 2024)
15-57063806-TC-T		TCF12-related craniosynostosis	Pathogenic (May 12, 2021)

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
0.676	0.324	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

Haploinsufficiency Scores

• pHI: 0.741
• hipred: Y
• hipred_score: 0.749
• ghis: 0.643

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

Mouse Genome Informatics

• Gene name: Tcf12
• Phenotype: immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype

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