TCF21

Summary

TCF21 (transcription factor 21, HGNC:11632) is a protein-coding gene on chromosome 6q23.2, encoding Transcription factor 21 (O43680). Involved in epithelial-mesenchymal interactions in kidney and lung morphogenesis that include epithelial differentiation and branching morphogenesis.

TCF21 encodes a transcription factor of the basic helix-loop-helix family. The TCF21 product is mesoderm specific, and expressed in embryonic epicardium, mesenchyme-derived tissues of lung, gut, gonad, and both mesenchymal and glomerular epithelial cells in the kidney. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 6943 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (No Known Disease Relationship, ClinGen)
• GWAS associations: 23
• Clinical variants (ClinVar): 24 total
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_003206

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11632
Approved symbol	TCF21
Name	transcription factor 21
Location	6q23.2
Locus type	gene with protein product
Status	Approved
Aliases	POD1, bHLHa23
Ensembl gene	ENSG00000118526
Ensembl biotype	protein_coding
OMIM	603306
Entrez	6943

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000237316, ENST00000367882, ENST00000903811

RefSeq mRNA: 2 — MANE Select: NM_003206 NM_003206, NM_198392

CCDS: CCDS5167

Canonical transcript exons

ENST00000367882 — 2 exons

Exon	Start	End
ENSE00001445855	133891713	133892257
ENSE00001889982	133889113	133889847

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 99.03.

FANTOM5 (CAGE): breadth broad, TPM avg 13.0521 / max 1692.4656, expressed in 495 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69853	13.0004	492
69855	0.0261	13
69854	0.0256	17

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.03	gold quality
right lung	UBERON:0002167	98.40	gold quality
upper lobe of left lung	UBERON:0008952	97.72	gold quality
upper lobe of lung	UBERON:0008948	97.48	gold quality
left ovary	UBERON:0002119	96.92	gold quality
right ovary	UBERON:0002118	96.22	gold quality
lower lobe of lung	UBERON:0008949	96.18	gold quality
lung	UBERON:0002048	95.10	gold quality
renal glomerulus	UBERON:0000074	94.95	gold quality
spleen	UBERON:0002106	94.92	gold quality
metanephros cortex	UBERON:0010533	94.75	gold quality
metanephric glomerulus	UBERON:0004736	94.44	gold quality
metanephros	UBERON:0000081	94.28	gold quality
ovary	UBERON:0000992	93.68	gold quality
right atrium auricular region	UBERON:0006631	93.45	gold quality
mucosa of stomach	UBERON:0001199	93.32	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.72	gold quality
lower esophagus	UBERON:0013473	92.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.10	gold quality
cardiac atrium	UBERON:0002081	91.86	gold quality
colonic epithelium	UBERON:0000397	91.23	gold quality
urinary bladder	UBERON:0001255	90.94	gold quality
adult organism	UBERON:0007023	90.93	gold quality
placenta	UBERON:0001987	90.90	gold quality
right coronary artery	UBERON:0001625	90.61	gold quality
transverse colon	UBERON:0001157	90.30	gold quality
sigmoid colon	UBERON:0001159	90.05	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.19	gold quality
left coronary artery	UBERON:0001626	89.10	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-8221	yes	1253.33
E-HCAD-10	yes	1152.21
E-MTAB-9906	yes	1101.75
E-HCAD-11	yes	895.60
E-MTAB-10662	yes	676.63
E-ANND-5	yes	594.00
E-MTAB-6701	yes	64.80
E-CURD-46	yes	25.71
E-ANND-3	yes	7.95

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets.

Target	Regulation
ACTA2
AR
CCN2	Unknown
CDKN1A	Repression
CKM
CNN1	Activation
CYP11A1
EIF3K
FN1	Activation
KISS1
NR5A1	Repression
RHO
ROCK1
RXFP2	Unknown
SF1
STAR
TAGLN	Activation

JASPAR motifs

Motif	Name	Family
MA1568.1	TCF21	Tal-related
MA1568.2	TCF21	Tal-related

JASPAR matrix evidence (PMIDs): PMID:25215497

Upstream regulators (CollecTRI, top): AP1, PITX2, SOX9, SRY

miRNA regulators (miRDB)

91 targeting TCF21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4762-5P	99.57	68.54	1424

Literature-anchored findings (GeneRIF, showing 40)

• epicardin/capsulin/Pod-1 functions as a negative regulator of differentiation of myoblasts through transcription in cell growth arrest and lineage-specific differentiation (PMID:12493738)
• analysis of TCF21 epigenetic regulation on 6q23-q24 in lung and head and neck cancer (PMID:16415157)
• Hypermethylation and decreased expression of TCF21 were tumor specific and very frequent in all NSCLCs, even early-stage disease. (PMID:20945327)
• Epigenetic downregulation of TCF21 is functionally involved in melanoma progression. (PMID:21771727)
• demonstrated that TCF21 was a significant prognosticator of cancer-specific survival (PMID:22862160)
• study found that POD-1/TCF21 acts as a transcriptional suppressor of SF-1 gene expression in adrenocortical carcinoma cells; a possible mechanism involved in repression of SF-1 expression is through POD-1 binding to the E-box sequence in the SF-1 promoter region (PMID:23313103)
• These findings, together with its stage- and primary site-dependent expression, turn TCF21 into a promising candidate biomarker in head and neck squamous cell carcinoma. (PMID:23529585)
• Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21. (PMID:23874238)
• these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2 (PMID:24676100)
• TCF21 inhibits the proliferation and migration and facilitates early apoptosis of A549 cells. (PMID:24758904)
• Results show that TARID, an antisense lncRNA activates TCF21 expression by inducing promoter demethylation. (PMID:25087872)
• Low TCF21 expression is associated with gastric cancer. (PMID:25156819)
• Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci consistent with the hypothesis that TCF21 may affect disease risk (PMID:26020271)
• our data provided the first evidence that TCF21 mRNA is significantly downregulated in breast cancer cell lines and tissues and regulates breast cancer cell proliferation and EMT. (PMID:26044559)
• TCF21 could inhibit the proliferation and migration of SMMC-7721 hepatocellular carcinoma cells and promote its apoptosis (PMID:26146055)
• The presence of significant hypermethylation of TCF21 supports the hypothesis that hypermethylation of TCF21 and/or decreased TARID expression lies within the pathogenic pathway of most CCSKs. (PMID:26158413)
• These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis. (PMID:26421305)
• TCF21 may function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in CRC development. (PMID:26435499)
• Association of miR-146a rs2910164 and TCF21 rs12190287 with CAD in an Iranian population. (PMID:26909569)
• TCF21 rs12190287 polymorphism can regulate TCF21 expression and may serve as a potential marker for genetic susceptibility to breast cancer. (PMID:27270650)
• There were significant differences in the genotype and allele frequencies of rs12190287 between the cases and controls in a Chinese population. Allele G of rs12190287 was significantly associated with an increased risk of Ventricular Septal Defects in a Chinese population. (PMID:28346832)
• TCF21 binds to AHR, promotes expression of AHR to upregulate inflammation-related genes in coronary artery smooth muscle. (PMID:28481916)
• we concluded that decreased mRNA expression of TCF21 is a predictor for poor prognosis in patients with lung adenocarcinoma. (PMID:28515486)
• Transcription Factor 21 is downregulated in adrenocortical carcinoma cells. Taken together, these findings support the hypothesis that Transcription Factor 21 is a regulator of steroidogenic factor 1 and is a tumor suppressor gene in pediatric and adult adrenocortical tumors. (PMID:28658440)
• Genetic polymorphisms of TCF21 are potentially predictive for osteosarcoma risk and outcomes. (PMID:28663539)
• The study revealed that restoration of TCF21 expression in 786-O clear cell renal cell carcinoma cell line results in decreased clonogenic proliferation and migration. (PMID:29080283)
• TCF21, a hypoxia-driven p53 target, functions as a tumor suppressor in uterine corpus endometrial cancer and presents as a therapeutic target for tumor treatment. (PMID:29608330)
• TCF21 is downregulated in ESCC, and its low expression is closely correlated with N stage and predicts a poor prognosis. TCF21 functions as a tumor suppressor in ESCC progression, and enhancement of its expression levels may be partly through promoting Kiss-1 expression to reverse EMT by modulating EMT-related gene expression. (PMID:29909422)
• TCF21 modulates Steroidogenic factor-1 and estrogen receptor beta expression through the recruitment of USF2 in endometriotic stromal cells. (PMID:30018006)
• hsa_circ_100395 regulates lung cancer cell proliferation, migration and invasion through modulating miR-1228/TCF21 pathway. (PMID:30176158)
• TCF21 inhibits gastric cancer growth and chemoresistance possibly through the AKT signaling pathway (PMID:30296564)
• Authors propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk. (PMID:30307970)
• Transcription factor 21 (TCF21) is downregulated in Cholangiocarcinoma (CCA) tissues or cells. (PMID:30920845)
• TCF21 interacts with JUN to regulate expression of two presumptive causal coronary disease genes, SMAD3 and CDKN2B-AS1. (PMID:31014396)
• Functional balance between Tcf21-Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines. (PMID:31241128)
• High TCF1 expression is associated with the pathogenesis of Fibrosis in Endometriosis. (PMID:31610174)
• Data show that transcription factor 21 (TCF21) directly interferes with formation and function of the myocardin (MYOCD)-serum response factor (SRF) complex. (PMID:31815603)
• TCF21 Promotes Luminal-Like Differentiation and Suppresses Metastasis in Bladder Cancer. (PMID:32122956)
• Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21. (PMID:32434219)
• Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping. (PMID:32513244)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcf21	ENSDARG00000036869
mus_musculus	Tcf21	ENSMUSG00000045680
rattus_norvegicus	Tcf21	ENSRNOG00000016700
drosophila_melanogaster	twi	FBGN0003900
drosophila_melanogaster	HLH54F	FBGN0022740
drosophila_melanogaster	Hand	FBGN0032209
drosophila_melanogaster	CG33557	FBGN0053557
caenorhabditis_elegans		WBGENE00001953

Paralogs (13): HAND1 (ENSG00000113196), TWIST1 (ENSG00000122691), TCF15 (ENSG00000125878), FERD3L (ENSG00000146618), TCF23 (ENSG00000163792), HAND2 (ENSG00000164107), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), TWIST2 (ENSG00000233608), SCX (ENSG00000260428), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Transcription factor 21 — O43680 (reviewed: O43680)

Alternative names: Capsulin, Class A basic helix-loop-helix protein 23, Epicardin, Podocyte-expressed 1

All UniProt accessions (1): O43680

UniProt curated annotations — full annotation on UniProt →

Function. Involved in epithelial-mesenchymal interactions in kidney and lung morphogenesis that include epithelial differentiation and branching morphogenesis. May play a role in the specification or differentiation of one or more subsets of epicardial cell types.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3 and binds the E box (5’-CANNTG-3’).

Subcellular location. Nucleus.

RefSeq proteins (2): NP_003197, NP_938206 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050283	E-box_TF_Regulators	Family

Pfam: PF00010

UniProt features (7 total): compositionally biased region 2, sequence conflict 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43680-F1	66.67	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 256 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_METANEPHROS_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_LUNG_MORPHOGENESIS, GOBP_SEX_DETERMINATION, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_METANEPHROS_DEVELOPMENT, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (30): negative regulation of transcription by RNA polymerase II (GO:0000122), ureteric bud development (GO:0001657), branching involved in ureteric bud morphogenesis (GO:0001658), morphogenesis of a branching structure (GO:0001763), kidney development (GO:0001822), vasculature development (GO:0001944), regulation of transcription by RNA polymerase II (GO:0006357), sex determination (GO:0007530), branchiomeric skeletal muscle development (GO:0014707), epithelial cell differentiation (GO:0030855), developmental process (GO:0032502), glomerulus development (GO:0032835), positive regulation of transcription by RNA polymerase II (GO:0045944), lung alveolus development (GO:0048286), spleen development (GO:0048536), embryonic digestive tract morphogenesis (GO:0048557), reproductive structure development (GO:0048608), gland development (GO:0048732), Sertoli cell differentiation (GO:0060008), roof of mouth development (GO:0060021), lung morphogenesis (GO:0060425), lung vasculature development (GO:0060426), bronchiole development (GO:0060435), diaphragm development (GO:0060539), respiratory system development (GO:0060541), negative regulation of androgen receptor signaling pathway (GO:0060766), metanephric mesenchymal cell differentiation (GO:0072162), metanephric glomerular capillary formation (GO:0072277), sex differentiation (GO:0007548), animal organ morphogenesis (GO:0009887)

GO Molecular Function (13): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), histone deacetylase binding (GO:0042826), bHLH transcription factor binding (GO:0043425), protein dimerization activity (GO:0046983), nuclear androgen receptor binding (GO:0050681), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
developmental process involved in reproduction	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
animal organ development	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
mesonephric tubule development	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
anatomical structure morphogenesis	1
multicellular organismal process	1
renal system development	1
system development	1
circulatory system development	1
muscle organ development	1
skeletal muscle tissue development	1
cell differentiation	1
epithelium development	1
biological_process	1
nephron development	1
positive regulation of DNA-templated transcription	1
lung development	1
hematopoietic or lymphoid organ development	1
digestive tract morphogenesis	1
embryonic organ morphogenesis	1
embryonic digestive tract development	1
reproductive system development	1
male gonad development	1
epithelial cell differentiation	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCF21	EYA4	O95677	806
TCF21	NKX3-2	P78367	789
TCF21	TBX18	O95935	769
TCF21	TCF12	Q99081	753
TCF21	TLX1	P31314	735
TCF21	WT1	P19544	722
TCF21	POSTN	Q15063	669
TCF21	TBX1	O43435	661
TCF21	MYF5	P13349	641
TCF21	SGK1	O00141	621
TCF21	ALDH1A2	O94788	576
TCF21	NKX2-5	P52952	568
TCF21	MYOD1	P15172	566
TCF21	GNB1L	Q9BYB4	548
TCF21	SEMA3D	O95025	542

IntAct

26 interactions, top by confidence:

A	B	Type	Score
TCF21	TCF12	psi-mi:“MI:0915”(physical association)	0.560
TCF21	MYOD1	psi-mi:“MI:0915”(physical association)	0.560
SDCBP	TCF21	psi-mi:“MI:0915”(physical association)	0.560
TCF21	APP	psi-mi:“MI:0915”(physical association)	0.560
TCF21	H1-5	psi-mi:“MI:0915”(physical association)	0.400
CCL1	TCF21	psi-mi:“MI:0915”(physical association)	0.370
IL3	TCF21	psi-mi:“MI:0915”(physical association)	0.370
HOXB6	TCF21	psi-mi:“MI:0915”(physical association)	0.370
APEX1	TCF21	psi-mi:“MI:0915”(physical association)	0.370
TCF21	GTF3C5	psi-mi:“MI:0915”(physical association)	0.370
TCF21	KLF15	psi-mi:“MI:0915”(physical association)	0.370
LMO4	TCF21	psi-mi:“MI:0915”(physical association)	0.370
TCF21	TCF12	psi-mi:“MI:0915”(physical association)	0.000
TCF21	MYOD1	psi-mi:“MI:0915”(physical association)	0.000
SDCBP	TCF21	psi-mi:“MI:0915”(physical association)	0.000
	TCF21	psi-mi:“MI:0915”(physical association)	0.000
tolR	TCF21	psi-mi:“MI:0915”(physical association)	0.000
y1093	TCF21	psi-mi:“MI:0915”(physical association)	0.000
poxB	TCF21	psi-mi:“MI:0915”(physical association)	0.000
TCF21	APLP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): APLP1 (Two-hybrid), MYOD1 (Two-hybrid), SDCBP (Two-hybrid), TCF12 (Two-hybrid), HIST1H1B (Proximity Label-MS), TCF21 (Two-hybrid), TCF21 (Two-hybrid), GTF3C5 (Two-hybrid), TCF21 (Two-hybrid), TCF3 (Two-hybrid), TCF4 (Two-hybrid), TCF12 (Two-hybrid), TCF3 (Affinity Capture-Western), TCF4 (Affinity Capture-Western), TCF12 (Affinity Capture-Western)

ESM2 similar proteins: A8E5T6, O35437, O43680, O57598, O73615, O93507, O96642, P13349, P13903, P13904, P15375, P16075, P16076, P17667, P19335, P23409, P24699, P24700, P32314, P57101, P57102, P59101, P70661, P79782, P79920, P97831, Q02576, Q10574, Q18277, Q23579, Q32PV5, Q4ZHW1, Q5E9S3, Q62282, Q6GNB7, Q6NYU3, Q6PUV5, Q6SYV5, Q7YS80, Q7ZSX3

Diamond homologs: A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P48985, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70661, P79765, P79782, P97831, P97832, Q02575, Q02576, Q02577, Q0VCE2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

24 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

415 predictions. Top by Δscore:

Variant	Effect	Δscore
6:133889847:GGTG:G	donor_loss	1.0000
6:133889848:G:GA	donor_loss	1.0000
6:133889850:GAGT:G	donor_loss	1.0000
6:133889848:G:GG	donor_gain	0.9900
6:133891808:G:GT	donor_gain	0.9900
6:133889843:ACCTG:A	donor_gain	0.9800
6:133889846:TG:T	donor_gain	0.9800
6:133889847:GG:G	donor_gain	0.9800
6:133891712:GAC:G	acceptor_gain	0.9800
6:133889845:CTG:C	donor_gain	0.9700
6:133891711:A:AG	acceptor_gain	0.9700
6:133891712:G:GG	acceptor_gain	0.9700
6:133891712:GACGT:G	acceptor_gain	0.9700
6:133891707:CCGCA:C	acceptor_loss	0.9600
6:133891708:CGCA:C	acceptor_loss	0.9600
6:133891709:GCAGA:G	acceptor_loss	0.9600
6:133891710:CA:C	acceptor_loss	0.9600
6:133891711:AGAC:A	acceptor_gain	0.9600
6:133891711:AGACG:A	acceptor_loss	0.9600
6:133891712:GACG:G	acceptor_gain	0.9600
6:133889844:CCTG:C	donor_gain	0.9500
6:133891708:C:A	acceptor_gain	0.9500
6:133891712:GA:G	acceptor_gain	0.9400
6:133891824:A:T	donor_gain	0.9400
6:133891313:GCCC:G	donor_gain	0.9200
6:133889830:A:G	donor_gain	0.9100
6:133889824:G:A	donor_gain	0.9000
6:133889849:T:G	donor_gain	0.8900
6:133890371:G:GG	donor_gain	0.8900
6:133889270:G:GT	donor_gain	0.8800

AlphaMissense

1174 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:133889638:C:A	R81S	1.000
6:133889648:C:A	A84D	1.000
6:133889652:C:A	N85K	1.000
6:133889652:C:G	N85K	1.000
6:133889653:G:C	A86P	1.000
6:133889657:G:C	R87P	1.000
6:133889659:G:A	E88K	1.000
6:133889660:A:C	E88A	1.000
6:133889660:A:G	E88G	1.000
6:133889660:A:T	E88V	1.000
6:133889661:G:C	E88D	1.000
6:133889661:G:T	E88D	1.000
6:133889663:G:C	R89P	1.000
6:133889665:G:C	A90P	1.000
6:133889668:C:A	R91S	1.000
6:133889668:C:G	R91G	1.000
6:133889668:C:T	R91C	1.000
6:133889672:T:A	M92K	1.000
6:133889672:T:G	M92R	1.000
6:133889673:G:A	M92I	1.000
6:133889673:G:C	M92I	1.000
6:133889673:G:T	M92I	1.000
6:133889675:G:C	R93P	1.000
6:133889681:T:A	L95Q	1.000
6:133889681:T:C	L95P	1.000
6:133889690:C:A	A98D	1.000
6:133889692:T:C	F99L	1.000
6:133889693:T:C	F99S	1.000
6:133889693:T:G	F99C	1.000
6:133889694:C:A	F99L	1.000

dbSNP variants (sampled 300 via entrez): RS1000160512 (6:133888306 T>C), RS1000435156 (6:133887827 G>A), RS1000572681 (6:133892373 G>T), RS1000840910 (6:133892615 C>T), RS1000945028 (6:133887166 AC>A), RS1001333040 (6:133888045 T>C), RS1001445422 (6:133893870 C>T), RS1001655207 (6:133887618 C>T), RS1001786698 (6:133892396 A>G), RS1001980280 (6:133893636 A>G), RS1002113672 (6:133892029 C>G,T), RS1002340232 (6:133889191 C>A,T), RS1002583146 (6:133894801 G>A), RS1002857534 (6:133894993 C>T), RS1003276457 (6:133890758 C>T)

Disease associations

OMIM: gene MIM:603306 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	No Known Disease Relationship	UD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000998_8	Coronary heart disease	1.000000e-12
GCST001587_2	Coronary heart disease	2.000000e-07
GCST002287_10	Coronary artery disease or ischemic stroke	2.000000e-08
GCST002289_4	Coronary artery disease	2.000000e-09
GCST002290_8	Coronary artery disease or large artery stroke	2.000000e-08
GCST003116_24	Coronary artery disease	2.000000e-11
GCST003542_172	Night sleep phenotypes	1.000000e-06
GCST004385_7	Systolic blood pressure	3.000000e-10
GCST004386_12	Diastolic blood pressure	2.000000e-06
GCST004387_6	Pulse pressure	7.000000e-06
GCST004388_12	Blood pressure traits (multi-trait analysis)	9.000000e-07
GCST004388_13	Blood pressure traits (multi-trait analysis)	1.000000e-07
GCST004787_34	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	6.000000e-14
GCST005195_131	Coronary artery disease	4.000000e-31
GCST005196_133	Coronary artery disease	3.000000e-31
GCST007928_6	Medication use (diuretics)	4.000000e-11
GCST007929_6	Medication use (calcium channel blockers)	4.000000e-10
GCST008062_124	Blood urea nitrogen levels	3.000000e-08
GCST009391_78	Metabolite levels	5.000000e-07
GCST010320_43	PR interval	2.000000e-08
GCST010321_26	PR interval	3.000000e-10
GCST010480_4	Coronary artery disease	1.000000e-12
GCST90014033_48	Haemorrhoidal disease	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0004462	PR interval

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases methylation	1
kojic acid	decreases expression	1
arsenite	increases methylation	1
mono(2-ethyl-5-oxohexyl)phthalate	increases methylation	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carmustine	decreases expression	1
Cytarabine	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects binding, increases expression	1
Methotrexate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases reaction, increases methylation	1
Tretinoin	increases expression	1
Valproic Acid	affects expression	1
Vitamin E	increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Genistein	decreases reaction, increases methylation	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7D1	SEES3-1V human TCF21, clone1	Embryonic stem cell	Male
CVCL_A7D2	SEES3-1V human TCF21, clone2	Embryonic stem cell	Male
CVCL_A7D3	SEES3-1V human TCF21, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE