ID3

Summary

ID3 (inhibitor of DNA binding 3, HGNC:5362) is a protein-coding gene on chromosome 1p36.12, encoding DNA-binding protein inhibitor ID-3 (Q02535). Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity.

The protein encoded by this gene is a helix-loop-helix (HLH) protein that can form heterodimers with other HLH proteins. However, the encoded protein lacks a basic DNA-binding domain and therefore inhibits the DNA binding of any HLH protein with which it interacts.

Source: NCBI Gene 3399 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 32 total
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types
• Transcription factor: yes — 38 downstream targets (CollecTRI)
• MANE Select transcript: NM_002167

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5362
Approved symbol	ID3
Name	inhibitor of DNA binding 3
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	HEIR-1, bHLHb25
Ensembl gene	ENSG00000117318
Ensembl biotype	protein_coding
OMIM	600277
Entrez	3399

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000374561, ENST00000463312, ENST00000486541, ENST00000856196, ENST00000856197, ENST00000918746, ENST00000918747, ENST00000918748, ENST00000918749, ENST00000918750, ENST00000956459

RefSeq mRNA: 1 — MANE Select: NM_002167 NM_002167

CCDS: CCDS237

Canonical transcript exons

ENST00000374561 — 3 exons

Exon	Start	End
ENSE00000758534	23558935	23559019
ENSE00001463824	23557926	23558415
ENSE00001463830	23559127	23559501

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 277.3299 / max 3050.6008, expressed in 1789 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10991	276.7604	1789
10992	0.4240	274
10993	0.1454	79

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	99.47	gold quality
descending thoracic aorta	UBERON:0002345	99.39	gold quality
left lobe of thyroid gland	UBERON:0001120	99.37	gold quality
thoracic aorta	UBERON:0001515	99.34	gold quality
ascending aorta	UBERON:0001496	99.33	gold quality
thyroid gland	UBERON:0002046	99.25	gold quality
right coronary artery	UBERON:0001625	99.21	gold quality
popliteal artery	UBERON:0002250	99.15	gold quality
tibial artery	UBERON:0007610	99.15	gold quality
left coronary artery	UBERON:0001626	99.13	gold quality
left uterine tube	UBERON:0001303	99.07	gold quality
right atrium auricular region	UBERON:0006631	98.96	gold quality
mucosa of stomach	UBERON:0001199	98.92	gold quality
mucosa of transverse colon	UBERON:0004991	98.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.71	gold quality
lower esophagus	UBERON:0013473	98.69	gold quality
omental fat pad	UBERON:0010414	98.65	gold quality
pituitary gland	UBERON:0000007	98.64	gold quality
fundus of stomach	UBERON:0001160	98.64	gold quality
apex of heart	UBERON:0002098	98.63	gold quality
adenohypophysis	UBERON:0002196	98.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.60	gold quality
tibial nerve	UBERON:0001323	98.46	gold quality
right lung	UBERON:0002167	98.40	gold quality
metanephros cortex	UBERON:0010533	98.36	gold quality
heart	UBERON:0000948	98.20	gold quality
prostate gland	UBERON:0002367	98.12	gold quality
transverse colon	UBERON:0001157	98.10	gold quality
heart left ventricle	UBERON:0002084	98.04	gold quality
body of stomach	UBERON:0001161	97.98	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	2876.79
E-GEOD-84465	yes	392.96
E-MTAB-3929	yes	79.29
E-MTAB-6075	yes	73.83
E-MTAB-9067	yes	15.02
E-MTAB-6678	yes	13.76
E-MTAB-9388	yes	11.40
E-MTAB-5061	yes	6.28
E-HCAD-25	yes	5.44
E-MTAB-6911	no	672.68
E-MTAB-10137	no	433.53
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

38 targets.

Target	Regulation
ADIPOQ
ALPL	Repression
BAX
BGLAP	Repression
BMP2
BMP4
CD8A
CDH1
CDKN1A	Activation
CDKN1B
CDKN2A	Activation
CKM
COL1A2	Repression
EGR1	Repression
EIF3K
FAS	Repression
FGF2
FOXP3	Activation
GAST
HES1	Activation
ID2
ID3
IL2RB
INHBA
JUN
MAPK1
MMP2
NGF
NOTCH1
NPTX1

Upstream regulators (CollecTRI, top): BCL11A, CTNNB1, E2F4, EGR1, GDF5, GDNF, ID1, ID2, ID3, KLF4, MYC, NFATC1, NFIA, NFIB, NFIX, PAX7, PRDM1, PTTG1, SMAD1, SMAD4, SMAD5, TCF3, TP63, ZBTB18

miRNA regulators (miRDB)

24 targeting ID3, 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-340-5P	100.00	72.50	4437
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-1972	97.67	67.38	1172
HSA-MIR-212-5P	96.83	67.43	950
HSA-MIR-4474-5P	94.23	67.95	568
HSA-MIR-5684	93.17	64.85	454

Literature-anchored findings (GeneRIF, showing 40)

• nuclear Id protein acts by sequestering pools of transiently diffusing bHLH protein to prevent reassociation with chromatin domains (PMID:12952978)
• Fluvastatin did not regulate p21 and p27, but down-regulated Id3 and p53 slightly. (PMID:15370294)
• Overexpression of Id3 enhances expression of ICAM-1 and E-selectin, and induces angiogenic processes such as transmigration, matrix metalloproteinase-2 and -9 expression, and tube formation in cultured vascular endothelial cells. (PMID:15494533)
• Id1, 2 and 3 might play a role in the early stages of hepatocarcinogenesis, but not in the development of advanced carcinoma, and might consequently be related to HCC dedifferentiation (PMID:15645115)
• Id1, 3 double-knockdown significantly impaired the ability of gastric cancer cells to form peritoneal metastasis (PMID:16271072)
• ultraviolet radiation-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells (PMID:16449966)
• ID proteins (ID1, ID2, ID3 and ID4) were significantly increased in Mecp2-deficient Rett syndrome brain; ID genes are ideal targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of Rett syndrome (PMID:16682435)
• PLZF upregulates apoptosis-inducer TP53INP1, ID1, and ID3 genes, and downregulates the apoptosis-inhibitor TERT gene (PMID:17537403)
• estrogen-induced tube formation in vascular endothelial cells requires the presence of Id3, a member of the helix-loop-helix family of transcriptional factors and estrogen increases Id3 phosphorylation via a redox-dependent process (PMID:18281048)
• RhoA/Rho-associated kinase signaling plays positive and negative roles in myogenic differentiation, mediated by MRTF-A/Smad-dependent transcription of the Id3 gene in a differentiation stage-specific manner (PMID:18477564)
• There is a mechanism whereby reactive oxygen species upregulation of Id3 relieves repression of bax via E-box-binding factors. (PMID:19054058)
• RNA interference demonstrated that Id3 regulates differentiation and cell cycle (increased Neuro-D6 and p21 mRNA) in neuroblastoma cells (PMID:19477940)
• role in the development of peritoneal metastasis of pancreatic cancer (PMID:19515385)
• The level of Id-3 protein expression was associated with the malignant potential of gastric tumors. (PMID:20080245)
• Results provide novel evidence that Id3 is an atheroprotective factor and link a common SNP in the human ID3 gene to loss of Id3 function and increased carotid intima-media thickness. (PMID:20185798)
• Id1/3 peptide aptamer could represent a nontoxic exogenous agent that can significantly provoke antiproliferative and apoptotic effects in breast cancer cells, which are associated with deregulated expression of Id1 and Id3. (PMID:20191379)
• expression of vFLIP decreased the expression levels of Id2 and Id3 as well as cyclin E and cyclin A compared with the vFLIP-null cells (PMID:20512523)
• ID3 plays a role as an apoptosis inducer in response to X-ray irradiation via the regulation of endogenous beta-catenin level. (PMID:21030215)
• In serum samples of lung cancer patients, galectin 1-mediated Id3 induces expression of interleukin (IL)-10 in functionally altered signal pathways of monocytes and monocyte-derived dendritic cells. (PMID:21191065)
• Study uniquely identifies ID1 and ID3 as negative regulators of the hPSC-hematopoietic transition from a hemogenic to a committed hematopoietic fate, and demonstrates that this is conserved between hESCs and hiPSCs. (PMID:21486943)
• the data establish dysregulation of the Id/bHLH axis as an early and sustained feature of ductal pathogenesis (PMID:21498546)
• The ID3 protein is expressed in prostate cancer, and is elevated with the increase of Gleason score. (PMID:21837949)
• EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. (PMID:21975932)
• Older muscle contained significantly more transcript for Forkhead Box O 1 (FoxO1, p=0.001), Inhibitor of DNA binding 1 (ID1, p=0.009), and Inhibitor of DNA Binding 3 (ID3, p=0.043) than young muscle. (PMID:21993163)
• Overexpression of Id3 triggered apoptosis in A549 lung adenocarcinoma cells, implicating Id3 in negative control of tumor growth. (PMID:22151756)
• Data show that regulation of p21 by ID1 and ID3 is a central mechanism preventing the accumulation of excess DNA damage and subsequent functional exhaustion of cancer-initiating cells (C-ICs). (PMID:22698403)
• Overexpression of Id3 markedly promoted the proliferation and invasive capacity of MCF-7 cells; however, these effects were significantly suppressed by the overexpression of FHL2. (PMID:22882857)
• These findings suggest an essential role of Id1 and Id3 in TGFbeta1 effects on proliferation and migration in prostate cancer cells. (PMID:23060149)
• Data indicate that ID2.K47A, ID2.Q55A and ID3.R52A, ID3.R60A had wildtype like expression levels in E. coli. (PMID:23119064)
• The findings suggested that cooperation between ID3 inactivation and immunoglobulin-MYC gene translocation is a hallmark of Burkitt lymphomagenesis. (PMID:23143595)
• Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy (PMID:23311395)
• increased Id1 and Id3 expression attenuates all three cyclin-dependent kinase inhibitors (CDKN2B, -1A, and -1B) resulting in a more aggressive PCa phenotype. (PMID:23342268)
• High ID3 expression is associated with medulloblastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors (PMID:23768125)
• Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in pulmonary artery smooth muscle cell. (PMID:23771884)
• ID3 mutations are recurrent events in double-hit B-cell lymphomas. (PMID:24222112)
• Importantly, the distinct ID3 expression patterns in acute leukemias (AL) indicate a specific deregulation of ID3 in the various types of AL and may support subtyping of AL. (PMID:24292846)
• study shows that Id2, Id3 and Id4 are each able to overcome TGF-beta dependence, and establish a role for Ids as key mediators of TGF-beta melanomagenesis (PMID:24343358)
• the combined immunohistochemical detection of VPREB3 and ID3 is applicable to the routine diagnostic in case of mature aggressive B-cell lymphomas. (PMID:24493312)
• Data indicate association of inhibitor of differentiation 3 (ID3) single nucleotide polymorphism rs11574 directly with coronary artery pathology. (PMID:24603695)
• Epigenetic changes in ID3, in combination with experiences of maltreatment, may confer risk for depression in children. (PMID:24655651)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	id3	ENSDARG00000054823
mus_musculus	Id3	ENSMUSG00000007872
rattus_norvegicus	Id3	ENSRNOG00000026124
drosophila_melanogaster	emc	FBGN0000575

Paralogs (3): ID2 (ENSG00000115738), ID1 (ENSG00000125968), ID4 (ENSG00000172201)

Protein

Protein identifiers

DNA-binding protein inhibitor ID-3 — Q02535 (reviewed: Q02535)

Alternative names: Class B basic helix-loop-helix protein 25, Helix-loop-helix protein HEIR-1, ID-like protein inhibitor HLH 1R21, Inhibitor of DNA binding 3, Inhibitor of differentiation 3

All UniProt accessions (1): Q02535

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Involved in myogenesis by inhibiting skeletal muscle and cardiac myocyte differentiation and promoting muscle precursor cells proliferation. Inhibits the binding of E2A-containing protein complexes to muscle creatine kinase E-box enhancer. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer.

Subunit / interactions. Homodimer, and heterodimer with other HLH proteins. Interacts with COPS5 and COPS7A. Interacts with IFI204. Interacts with GATA4 and NKX2-5. Interacts with ANKRD2; both proteins cooperate in myoblast differentiation. Interacts with CLOCK and BMAL1.

Subcellular location. Nucleus.

Tissue specificity. Expressed abundantly in lung, kidney and adrenal gland, but not in adult brain.

Induction. By phorbol 12-myristate 13-acetate (PMA).

RefSeq proteins (1): NP_002158* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR026052	DNA-bd_prot-inh	Family
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00010

UniProt features (7 total): sequence variant 2, helix 2, chain 1, domain 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2LFH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02535-F1	68.61	0.23

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9031628	NGF-stimulated transcription

MSigDB gene sets: 521 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_BCELL_UP, GOBP_CIRCADIAN_RHYTHM, E2F_Q4, FXR_IR1_Q6, E2F_Q4_01, GOBP_EPITHELIUM_DEVELOPMENT, KOBAYASHI_EGFR_SIGNALING_24HR_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_METANEPHROS_DEVELOPMENT, E2F4DP1_01, GOBP_CELLULAR_RESPONSE_TO_LIPID, XU_GH1_AUTOCRINE_TARGETS_UP

GO Biological Process (20): negative regulation of transcription by RNA polymerase II (GO:0000122), metanephros development (GO:0001656), regulation of DNA replication (GO:0006275), central nervous system development (GO:0007417), heart development (GO:0007507), muscle organ development (GO:0007517), circadian rhythm (GO:0007623), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), neuron differentiation (GO:0030182), epithelial cell differentiation (GO:0030855), notochord development (GO:0030903), odontogenesis (GO:0042476), positive regulation of apoptotic process (GO:0043065), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), negative regulation of myoblast differentiation (GO:0045662), negative regulation of osteoblast differentiation (GO:0045668), negative regulation of DNA-templated transcription (GO:0045892), cellular response to leptomycin B (GO:0072750), rhythmic process (GO:0048511)

GO Molecular Function (7): transcription corepressor activity (GO:0003714), protein domain specific binding (GO:0019904), bHLH transcription factor binding (GO:0043425), protein dimerization activity (GO:0046983), transcription regulator inhibitor activity (GO:0140416), leptomycin B binding (GO:1901707), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nuclear Events (kinase and transcription factor activation)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	3
negative regulation of DNA-templated transcription	2
animal organ development	2
gene expression	2
cell differentiation	2
negative regulation of cell differentiation	2
protein binding	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
kidney development	1
DNA replication	1
regulation of DNA metabolic process	1
nervous system development	1
system development	1
circulatory system development	1
muscle structure development	1
rhythmic process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
generation of neurons	1
epithelium development	1
embryonic organ development	1
animal organ morphogenesis	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
myoblast differentiation	1
regulation of myoblast differentiation	1
osteoblast differentiation	1
regulation of osteoblast differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
cellular response to fatty acid	1
response to leptomycin B	1
biological_process	1
transcription coregulator activity	1
DNA-binding transcription factor binding	1
transcription regulator activity	1

Protein interactions and networks

STRING

1390 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ID3	TCF3	P15883	758
ID3	PAX5	Q02548	758
ID3	NBL1	P41271	697
ID3	ZBTB18	Q99592	681
ID3	CD79A	P11912	626
ID3	CD27	P26842	599
ID3	PRDM1	O75626	591
ID3	TCF4	P15884	585
ID3	EOMES	O95936	581
ID3	BCL6	P41182	580
ID3	TCF7	P36402	577
ID3	PRKCH	P24723	562
ID3	WNT5A	P41221	546
ID3	TBX21	Q9UL17	544
ID3	TCF12	Q99081	529

IntAct

103 interactions, top by confidence:

A	B	Type	Score
TCF4	ID3	psi-mi:“MI:0915”(physical association)	0.800
ID3	TCF4	psi-mi:“MI:0915”(physical association)	0.800
ID3	TCF12	psi-mi:“MI:0915”(physical association)	0.740
TCF12	ID3	psi-mi:“MI:0915”(physical association)	0.740
ID3	TCF12	psi-mi:“MI:0915”(physical association)	0.670
FHL2	ID3	psi-mi:“MI:0915”(physical association)	0.670
ID3	FHL2	psi-mi:“MI:0915”(physical association)	0.670
TCF3	ID3	psi-mi:“MI:0915”(physical association)	0.560
ID3	FAM74A1	psi-mi:“MI:0915”(physical association)	0.560
BOLA2-SMG1P6	ID3	psi-mi:“MI:0915”(physical association)	0.560
TCF4	ID3	psi-mi:“MI:0915”(physical association)	0.560
MYF5	ID3	psi-mi:“MI:0915”(physical association)	0.560
LMO4	ID3	psi-mi:“MI:0915”(physical association)	0.560
FRS3	ID3	psi-mi:“MI:0915”(physical association)	0.560
ID3	CREB5	psi-mi:“MI:0915”(physical association)	0.560
ID3	C22orf39	psi-mi:“MI:0915”(physical association)	0.560
ID3	GUCD1	psi-mi:“MI:0915”(physical association)	0.560
ID3	KRTAP26-1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (77): TCF4 (Two-hybrid), TCF3 (Two-hybrid), TCF12 (Two-hybrid), FAM74A1 (Two-hybrid), ID3 (Affinity Capture-RNA), ID3 (Affinity Capture-Western), ID3 (Reconstituted Complex), ID3 (Affinity Capture-MS), TCEB1 (Affinity Capture-Western), VHL (Affinity Capture-Western), ID3 (Affinity Capture-MS), ID3 (Affinity Capture-RNA), ID3 (Co-localization), ID3 (Two-hybrid), ID3 (Two-hybrid)

ESM2 similar proteins: A8E5T6, O13125, O13126, O35437, O43680, O57598, O60682, O73615, O88940, P12979, P13903, P15173, P15375, P19335, P23409, P34060, P41133, P41138, P49812, P59101, P70562, P70661, P79782, P97831, Q01795, Q02535, Q02576, Q02577, Q16559, Q20561, Q32PV5, Q3YFL6, Q5E981, Q5E9S3, Q62282, Q6GNB7, Q6VNZ9, Q712G9, Q7YS80, Q8AW52

Diamond homologs: P18491, P20067, P41133, P41134, P41135, P41136, P41137, P41138, P41139, P47928, Q02363, Q02535, Q06AV5, Q2VIU1, Q3ZC46, Q4R5J7, Q5E981, Q5RCH7, Q66J78, Q688C4, Q6GL62, Q6PBD7, Q712G9, Q7SZ28, Q7ZXF3, Q91399, Q9PWJ5, O73823, O93507, P17542, P22091, P24899, Q6QHK4, O73615, O96004, P57100, P97832, Q0VCE2, Q28555, Q64279

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
GDF5	“up-regulates quantity by expression”	ID3	“transcriptional regulation”
PTK2B	“up-regulates quantity”	ID3	phosphorylation
CDK2	down-regulates	ID3	phosphorylation
ID3	“down-regulates activity”	TCF3	binding
ID3	“down-regulates activity”	MYOD/HEB	binding
ID3	“down-regulates activity”	TCF12	binding
ID3	“down-regulates activity”	MYOD/E2-2	binding
ID3	“down-regulates activity”	MYOD/E12E47	binding
ID3	“down-regulates activity”	TCF4	binding
NFIA	“down-regulates quantity”	ID3	“transcriptional regulation”
NFIB	“down-regulates quantity”	ID3	“transcriptional regulation”
NFIX	“down-regulates quantity”	ID3	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	ID3	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — BL, DLBCLNOS, MLYM, NHL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

318 predictions. Top by Δscore:

Variant	Effect	Δscore
1:23558931:TCACC:T	donor_loss	1.0000
1:23558932:CACC:C	donor_loss	1.0000
1:23558933:A:AC	donor_gain	1.0000
1:23558933:AC:A	donor_gain	1.0000
1:23558934:C:CC	donor_gain	1.0000
1:23558934:C:CG	donor_loss	1.0000
1:23558934:CC:C	donor_gain	1.0000
1:23558934:CCT:C	donor_gain	1.0000
1:23558934:CCTG:C	donor_gain	1.0000
1:23558934:CCTGG:C	donor_gain	1.0000
1:23559016:CTGT:C	acceptor_gain	1.0000
1:23559020:C:CC	acceptor_gain	1.0000
1:23559024:T:C	acceptor_gain	1.0000
1:23559024:T:TC	acceptor_gain	1.0000
1:23559121:GCTTA:G	donor_loss	1.0000
1:23559122:CTTAC:C	donor_loss	1.0000
1:23559123:TTAC:T	donor_loss	1.0000
1:23559124:TAC:T	donor_loss	1.0000
1:23559126:C:CG	donor_loss	1.0000
1:23559017:TGT:T	acceptor_gain	0.9900
1:23559018:GT:G	acceptor_gain	0.9900
1:23559018:GTCTG:G	acceptor_loss	0.9900
1:23559020:C:CA	acceptor_loss	0.9900
1:23559021:T:C	acceptor_loss	0.9900
1:23558421:C:CT	acceptor_gain	0.9800
1:23558422:G:T	acceptor_gain	0.9800
1:23559633:T:TA	donor_gain	0.9800
1:23558413:GTTC:G	acceptor_loss	0.9700
1:23558414:TT:T	acceptor_gain	0.9700
1:23558416:C:A	acceptor_loss	0.9700

AlphaMissense

757 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:23559197:A:G	I77T	0.998
1:23559275:A:G	L51P	0.998
1:23559275:A:T	L51Q	0.998
1:23559188:A:G	L80P	0.997
1:23559197:A:T	I77N	0.996
1:23559206:A:T	I74N	0.996
1:23559218:A:G	L70P	0.996
1:23559266:A:G	L54P	0.996
1:23559197:A:C	I77S	0.993
1:23559218:A:T	L70Q	0.993
1:23559206:A:C	I74S	0.991
1:23559275:A:C	L51R	0.991
1:23559188:A:T	L80Q	0.990
1:23559221:A:G	I69T	0.990
1:23559221:A:C	I69S	0.989
1:23559285:A:C	Y48D	0.989
1:23559233:C:A	S65I	0.988
1:23559285:A:G	Y48H	0.986
1:23559194:A:G	L78P	0.985
1:23559210:C:G	V73L	0.984
1:23559214:C:A	Q71H	0.984
1:23559214:C:G	Q71H	0.984
1:23559215:T:G	Q71P	0.984
1:23559288:A:G	C47R	0.982
1:23559201:A:G	Y76H	0.980
1:23559209:A:T	V73D	0.980
1:23559218:A:C	L70R	0.979
1:23559285:A:T	Y48N	0.979
1:23559184:C:A	Q81H	0.977
1:23559184:C:G	Q81H	0.977

dbSNP variants (sampled 300 via entrez): RS1000046510 (1:23560623 C>T), RS1000949440 (1:23557873 G>A), RS1001053944 (1:23557477 T>C), RS1001497265 (1:23559821 C>T), RS1001716370 (1:23559700 C>T), RS1002279686 (1:23559937 A>C), RS1002803538 (1:23557778 C>T), RS1002830406 (1:23558730 A>T), RS1003835663 (1:23558013 C>T), RS1004054947 (1:23557856 C>T), RS1004082428 (1:23561101 G>A,C), RS1004384608 (1:23560197 G>A), RS1004434248 (1:23561294 G>A), RS1004721103 (1:23561323 A>G), RS1004844480 (1:23558664 T>A)

Disease associations

OMIM: gene MIM:600277 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

140 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	7
Estradiol	affects cotreatment, decreases expression	6
Particulate Matter	increases abundance, affects cotreatment, increases expression, decreases expression	6
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, increases expression	4
Tretinoin	affects expression, increases expression	4
bisphenol A	decreases expression, decreases methylation, increases expression	3
Air Pollutants	decreases expression, increases abundance	3
Benzo(a)pyrene	increases expression, increases methylation	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
Aflatoxin B1	affects expression, increases expression	3
Genistein	decreases expression, increases expression	3
methylselenic acid	decreases expression, increases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
Decitabine	affects expression, increases expression	2
Aerosols	decreases expression	2
Ethanol	affects cotreatment, decreases expression, increases abundance, increases expression	2
Cisplatin	affects expression, decreases expression	2
Doxorubicin	increases expression	2
Fluorouracil	increases expression	2
Methotrexate	increases expression, decreases expression	2
Progesterone	increases expression	2
Dronabinol	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
securinine	increases expression	1
methylmercuric chloride	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1

Cellosaurus cell lines

32 cell lines: 25 transformed cell line, 5 embryonic stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3D2	SEES3-1V human ID3, clone1	Embryonic stem cell	Male
CVCL_A3D3	SEES3-1V human ID3, clone2	Embryonic stem cell	Male
CVCL_A3D4	SEES3-1V human ID3, clone3	Embryonic stem cell	Male
CVCL_AW26	K562 eGFP-ID3	Cancer cell line	Female
CVCL_B371	TL-1	Cancer cell line	Male
CVCL_B7TU	e-hChon-1	Transformed cell line	Female
CVCL_B7TV	e-hChon-2	Transformed cell line	Female
CVCL_B7TW	e-hChon-3	Transformed cell line	Female
CVCL_B7U0	e-hDFib3	Transformed cell line	Male
CVCL_B7U3	e-hFib-3	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome