Human Gene Module / Chromosome 15 / TCF12

TCF12transcription factor 12

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 10
Rare Variants / Common Variants
29 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
15q21.3
Associated Disorders
-
Relevance to Autism

Trio-based whole-exome sequencing of 168 patients with low-functioning ASD at Sun Yat-sen Memorial Hospital in Wu et al., 2025 identified a de novo loss-of-function variant in the TCF12 gene in a patient clinically diagnosed with ASD based on DSM-5 criteria and presenting with global developmental delay/intellectual disability. Additional de novo loss-of-function variants, as well as a de novo missense variant prediced to be deleterious by CADD, REVEL, and MPC, were previously reported in TCF12 in ASD probands from the MSSNG cohort, the SPARK cohort, and the Autism Sequencing Consortium (Yuen et al., 2016; Zhou et al., 2022; Fu et al., 2022; Trost et al., 2022). TCF12 was identified in Wang et al., 2020 as an novel NDD risk gene, with ultra-rare likely gene-disruptive variants reaching FDR significance following a combined analysis of new ASD and NDD cases with published data. Autism spectrum disorder was been reported in a subset of individuals with craniosynostosis 3 (Sharma et al., 2013; Paumard-Hernndez et al., 2015).

Molecular Function

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. Heterozygous mutations in this gene are responsible for craniosynostosis 3 (OMIM 615314).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TCF12 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Vikram P Sharma et al. (2013) No ASD
2 Support - Beatriz Paumard-Hernández et al. (2015) No ASD
3 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
4 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
5 Support - Zhou X et al. (2022) Yes -
6 Support - Fu JM et al. (2022) Yes -
7 Support - Chan AJS et al. (2022) Yes -
8 Support - Trost B et al. (2022) Yes -
9 Primary - Ruohao Wu et al. (2025) Yes -
10 Support - Giancarlo Mancuso et al. (2026) Yes -
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.446C>G p.Ser149Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.921C>A p.Tyr307Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1876C>T p.Arg626Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.390+1G>A p.? splice_site_variant De novo - - 33004838 Wang T et al. (2020)
c.590C>T p.Pro197Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.616C>T p.Arg206Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.931delT p.Ser311fs frameshift_variant De novo - - 35982160 Fu JM et al. (2022)
c.1018G>C p.Gly340Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1094G>A p.Gly365Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1454G>A p.Arg485Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1486G>T p.Asp496Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1838G>A p.Arg613His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2027A>G p.Glu676Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1433C>G p.Ser478Ter stop_gained De novo - Simplex 36368308 Trost B et al. (2022)
c.1036-1G>T p.? splice_site_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.1189-2A>G p.? splice_site_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.1837C>T p.Arg613Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.953G>A p.Gly318Glu missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.694del p.His232ThrfsTer13 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1877G>A p.Arg626Gln missense_variant De novo - Multiplex 33004838 Wang T et al. (2020)
c.281delA p.His94LeufsTer10 frameshift_variant De novo - - 41127290 Ruohao Wu et al. (2025)
c.686-1G>C - splice_site_variant De novo - Simplex 41596607 Giancarlo Mancuso et al. (2026)
c.160delA Arg54GlufsTer33 frameshift_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.1099C>T p.Pro367Ser missense_variant Familial Maternal Simplex 33004838 Wang T et al. (2020)
c.1704del p.Ser569ProfsTer22 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.356del p.Leu119ArgfsTer16 frameshift_variant De novo - Multiplex 33004838 Wang T et al. (2020)
c.1808G>A p.Arg603Gln missense_variant Familial Paternal Multiplex 33004838 Wang T et al. (2020)
c.675del p.Phe226LeufsTer19 frameshift_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.1106_1107insG p.Leu370SerfsTer21 frameshift_variant Familial Maternal Simplex 36309498 Chan AJS et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2025
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.60927811408287

Ranking 263/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.97389993424598

Ranking 2275/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94394171593086

Ranking 15882/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.006734670735342

Ranking 8897/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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