TNS3

Summary

TNS3 (tensin 3, HGNC:21616) is a protein-coding gene on chromosome 7p12.3, encoding Tensin-3 (Q68CZ2). May act as a protein phosphatase and/or a lipid phosphatase. It is a selective cancer dependency (DepMap: 11.8% of cell lines).

Predicted to enable guanyl-nucleotide exchange factor adaptor activity. Predicted to be involved in positive regulation of Rac protein signal transduction and positive regulation of guanyl-nucleotide exchange factor activity. Predicted to act upstream of or within several processes, including bone resorption; negative regulation of Rho protein signal transduction; and podosome assembly. Located in cytosol and focal adhesion.

Source: NCBI Gene 64759 — RefSeq curated summary.

At a glance

• GWAS associations: 59
• Clinical variants (ClinVar): 306 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 11.8% of screened cell lines
• MANE Select transcript: NM_022748

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21616
Approved symbol	TNS3
Name	tensin 3
Location	7p12.3
Locus type	gene with protein product
Status	Approved
Aliases	TEM6, H_NH0549I23.2, FLJ13732
Ensembl gene	ENSG00000136205
Ensembl biotype	protein_coding
OMIM	606825
Entrez	64759

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 17 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000311160, ENST00000413551, ENST00000415929, ENST00000428457, ENST00000434451, ENST00000442536, ENST00000450444, ENST00000457718, ENST00000469470, ENST00000474346, ENST00000485555, ENST00000705350, ENST00000705472, ENST00000705473, ENST00000705474, ENST00000887086, ENST00000887087, ENST00000887088, ENST00000939401, ENST00000939402, ENST00000947274

RefSeq mRNA: 3 — MANE Select: NM_022748 NM_001410877, NM_001410878, NM_022748

CCDS: CCDS5506, CCDS94098, CCDS94100

Canonical transcript exons

ENST00000311160 — 31 exons

Exon	Start	End
ENSE00000832696	47280164	47280190
ENSE00000832697	47280286	47280354
ENSE00000832698	47283697	47283865
ENSE00000832699	47291955	47292032
ENSE00000832700	47292828	47292905
ENSE00000832701	47293733	47293828
ENSE00000832702	47297082	47297213
ENSE00001010570	47346187	47346356
ENSE00001010573	47344924	47345038
ENSE00001010575	47302950	47303584
ENSE00001010576	47302186	47302272
ENSE00001010582	47344755	47344838
ENSE00001010583	47304832	47305003
ENSE00001202244	47368365	47369621
ENSE00001487432	47582051	47582111
ENSE00001535379	47275154	47278220
ENSE00001668358	47411727	47411802
ENSE00001688697	47413937	47413997
ENSE00001729147	47428312	47428376
ENSE00001775242	47424101	47424184
ENSE00001797590	47415094	47415206
ENSE00001805115	47437263	47437313
ENSE00003482561	47400393	47400458
ENSE00003488672	47400785	47400914
ENSE00003539175	47396800	47396904
ENSE00003788803	47435282	47435404
ENSE00003993393	47442003	47442055
ENSE00003993394	47529036	47529147
ENSE00003993396	47481103	47481141
ENSE00003993397	47506907	47506944
ENSE00003993402	47439487	47439658

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.1016 / max 381.6677, expressed in 1622 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84055	20.6566	1602
84035	6.4223	266
84062	1.6551	379
84022	1.2092	421
84056	0.9519	594
84057	0.7693	462
84023	0.6647	322
84058	0.6155	330
84036	0.3804	112
84054	0.3701	215

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal glomerulus	UBERON:0000074	99.58	gold quality
metanephric glomerulus	UBERON:0004736	99.58	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.51	gold quality
tibia	UBERON:0000979	99.42	gold quality
parotid gland	UBERON:0001831	99.40	gold quality
kidney epithelium	UBERON:0004819	98.62	gold quality
cartilage tissue	UBERON:0002418	98.60	gold quality
renal medulla	UBERON:0000362	98.30	gold quality
olfactory bulb	UBERON:0002264	98.26	gold quality
visceral pleura	UBERON:0002401	98.22	gold quality
inferior olivary complex	UBERON:0002127	98.09	gold quality
trigeminal ganglion	UBERON:0001675	98.04	gold quality
endothelial cell	CL:0000115	97.95	gold quality
placenta	UBERON:0001987	97.82	gold quality
nephron tubule	UBERON:0001231	97.77	gold quality
dorsal root ganglion	UBERON:0000044	97.69	gold quality
metanephros	UBERON:0000081	97.60	gold quality
pigmented layer of retina	UBERON:0001782	97.59	gold quality
retina	UBERON:0000966	97.57	gold quality
lower lobe of lung	UBERON:0008949	97.51	gold quality
cranial nerve II	UBERON:0000941	97.50	gold quality
adult organism	UBERON:0007023	97.08	gold quality
trabecular bone tissue	UBERON:0002483	96.76	gold quality
epithelial cell of pancreas	CL:0000083	96.75	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.63	gold quality
germinal epithelium of ovary	UBERON:0001304	96.62	gold quality
medulla oblongata	UBERON:0001896	96.62	gold quality
lateral globus pallidus	UBERON:0002476	96.57	gold quality
ileal mucosa	UBERON:0000331	96.52	gold quality
decidua	UBERON:0002450	96.50	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	2299.29
E-ANND-3	yes	12.44
E-GEOD-124858	no	117.34

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting TNS3, 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-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• Tensin3 may function as a platform for the disassembly of EGF-related signaling complexes at focal adhesions. (PMID:15140944)
• Data show that EGF downregulates tensin-3 expression, and concomitantly upregulates cten, a tensin family member that lacks the actin-binding domain. (PMID:17643115)
• TNS3-EXOC6B and EXOC6B-TNS3 fusion transcripts are detected in a premature male newborn with a complex multisystemic phenotype associated with a balanced translocation. (PMID:18424204)
• Tensin3 mRNA is expressed abundantly in all twelve functional adenomas at almost the same level as in normal thyroid tissue. (PMID:18561090)
• Tensins may represent a novel group of metastasis suppressors in the kidney, the loss of which leads to greater tumor cell motility and consequent metastasis. (PMID:19194507)
• These results reveal a differential methylation pattern in the TNS3 promoter occurring in human renal cell carcinoma. (PMID:23803643)
• The phenotypic changes observed in proband cells may arise from TNS3 haploinsufficiency, causing partial loss of full-length Tensin3 protein. Tensin3 plays a rol in cytoskeletal organisation and cell motility. (PMID:23809228)
• The depletion of tensin-3 suppressed breast cancer cell invasiveness. (PMID:25814362)
• A phosphorylation-mediated molecular switch comprising DLC), TNS3, PTEN and PI3K controls the spatiotemporal activation of Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. (PMID:26166433)
• Our work identifies Tns3 as a crucial focal adhesion component regulated by, and functionally contributing to, the switch between adhesive and non-adhesive states in MDA-MB-468 cancer cells. (PMID:28515231)
• These findings suggested a critical role of MSI1-TNS3 axis in regulating glioblastoma migration. (PMID:28821879)
• Tensin-3 Regulates Integrin-Mediated Proliferation and Differentiation of Tonsil-Derived Mesenchymal Stem Cells. (PMID:31905841)
• MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity. (PMID:33824309)
• PEAK1 Y635 phosphorylation regulates cell migration through association with Tensin3 and integrins. (PMID:35687021)
• Tensin Regulates Fundamental Biological Processes by Interacting with Integrins of Tonsil-Derived Mesenchymal Stem Cells. (PMID:35954177)
• Abnormal TNS3 gene methylation in patients with congenital scoliosis. (PMID:35987623)
• Tensin-3 is involved in osteogenic versus adipogenic fate of human bone marrow stromal cells. (PMID:37668682)
• Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination. (PMID:38109544)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tns3	ENSMUSG00000020422
rattus_norvegicus	Tns3	ENSRNOG00000025695

Paralogs (6): TNS1 (ENSG00000079308), HVCN1 (ENSG00000122986), TPTE2 (ENSG00000132958), TMEM266 (ENSG00000169758), PTEN (ENSG00000171862), TPTE (ENSG00000274391)

Protein

Protein identifiers

Tensin-3 — Q68CZ2 (reviewed: Q68CZ2)

Alternative names: Tensin-like SH2 domain-containing protein 1, Tumor endothelial marker 6

All UniProt accessions (11): A0A994J4W0, A0A994J537, A0A994J7F3, A0A994J7T8, C9JHU5, C9JTD0, C9JUW5, C9JWN9, Q68CZ2, E9PCX8, H7BZ64

UniProt curated annotations — full annotation on UniProt →

Function. May act as a protein phosphatase and/or a lipid phosphatase. Involved in the dissociation of the integrin-tensin-actin complex. EGF activates TNS4 and down-regulates TNS3 which results in capping the tail of ITGB1. Increases DOCK5 guanine nucleotide exchange activity towards Rac and plays a role in osteoclast podosome organization. Enhances RHOA activation in the presence of DLC1. Required for growth factor-induced epithelial cell migration; growth factor stimulation induces TNS3 phosphorylation which changes its binding preference from DLC1 to the p85 regulatory subunit of the PI3K kinase complex, displacing PI3K inhibitor PTEN and resulting in translocation of the TNS3-p85 complex to the leading edge of migrating cells to promote RAC1 activation. Meanwhile, PTEN switches binding preference from p85 to DLC1 and the PTEN-DLC1 complex translocates to the posterior of migrating cells to activate RHOA. Acts as an adapter protein by bridging the association of scaffolding protein PEAK1 with integrins ITGB1, ITGB3 and ITGB5 which contributes to the promotion of cell migration. Controls tonsil-derived mesenchymal stem cell proliferation and differentiation by regulating the activity of integrin ITGB1.

Subunit / interactions. Interacts with EGFR; EGF promotes the interaction with EGFR. Interacts with PTK2/FAK1 and BCAR1. Tyrosine phosphorylation is critical for these interactions. Interacts with Rho GTPase-activating protein DLC1 and with the regulatory p85 subunit of the PI3K kinase complex; in resting cells, interacts (via C2 tensin-type domain) with DLC1 but, following growth factor stimulation, TNS3 is phosphorylated which leads to weakened interaction with DLC1 and enhanced interaction (via C2 tensin-type domain) with p85 while DLC1 interaction with PTEN increases. Interacts (when phosphorylated on the SH2 domain) with integrins ITGB1, ITGB3 and ITGB5 and with scaffolding protein PEAK1 (phosphorylated on ‘Tyr-635’); mediates the association of PEAK1 with ITGB1, ITGB3 and ITGB5. Interacts (via N-terminus) with DOCK5 (via N-terminus); the interaction increases DOCK5 guanine nucleotide exchange activity towards Rac. Interacts with receptor tyrosine kinase MET.

Subcellular location. Cell junction. Focal adhesion. Cell projection. Podosome.

Tissue specificity. Expressed in umbilical vein endothelial cells, epithelial cells, and fibroblasts cells (at protein level). Highly expressed in thyroid, kidney and placenta. Low expression in heart, skeletal muscle, spleen, liver, and lung. Expressed at higher levels in tonsil-derived mesenchymal stem cells (MSCs) than in adipose tissue-derived MSCs or bone marrow-derived MSCs. Expressed in tumor endothelial cells. Expression seems to be down-regulated in thyroid tumor tissues and in anaplastic carcinomas.

Post-translational modifications. Phosphorylated on Ser/Thr and Tyr residues. Phosphorylated on Thr-323 in the C2-type tensin domain following EGF stimulation which changes its binding preference from DLC1 to the p85 regulatory subunit of the PI3K kinase complex. EGF induces tyrosine phosphorylation in a time- and dose-dependent manner. Phosphorylation of the SH2 domain enhances interaction with PEAK1.

Induction. Down-regulated by EGF.

Similarity. Belongs to the PTEN phosphatase protein family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q68CZ2-1	1	yes
Q68CZ2-2	2
Q68CZ2-3	3
Q68CZ2-4	4

RefSeq proteins (3): NP_001397806, NP_001397807, NP_073585* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000387	Tyr_Pase_dom	Domain
IPR000980	SH2	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013625	PTB	Domain
IPR014020	Tensin_C2-dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029023	Tensin_phosphatase	Domain
IPR033929	Tensin_PTB	Domain
IPR035012	Tensin-like_SH2	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051484	Tensin_PTEN_phosphatase	Family

Pfam: PF00017, PF08416, PF10409

UniProt features (58 total): modified residue 21, compositionally biased region 7, region of interest 6, mutagenesis site 6, splice variant 5, sequence conflict 5, domain 4, sequence variant 3, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9QN7	X-RAY DIFFRACTION	2.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q68CZ2-F1	58.05	0.24

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (21): 323, 332, 361, 440, 516, 571, 632, 649, 660, 687, 690, 735, 776, 780, 811, 866, 901, 1149, 1154, 1293 …

Mutagenesis-validated functional residues (6):

Position	Phenotype
321	constitutive interaction with p85 and interaction with dlc1 after egf stimulation.
323	abolishes phosphorylation. abolishes interaction with dlc1 and p85.
323	constitutive interaction with p85.
1173	significantly reduced interaction with peak1; when associated with f-1206 and f-1256.
1206	significantly reduced interaction with peak1; when associated with f-1173 and f-1256.
1256	significantly reduced interaction with peak1; when associated with f-1173 and f-1206.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-8875513	MET interacts with TNS proteins
R-HSA-162582	Signal Transduction
R-HSA-6806834	Signaling by MET
R-HSA-8875878	MET promotes cell motility
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 254 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MODULE_169, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_REGULATION_OF_RAC_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, TIEN_INTESTINE_PROBIOTICS_24HR_UP, HOEBEKE_LYMPHOID_STEM_CELL_UP, JAATINEN_HEMATOPOIETIC_STEM_CELL_UP

GO Biological Process (2): positive regulation of Rac protein signal transduction (GO:0035022), dephosphorylation (GO:0016311)

GO Molecular Function (6): phosphoprotein phosphatase activity (GO:0004721), actin binding (GO:0003779), protein binding (GO:0005515), zinc ion binding (GO:0008270), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (8): podosome (GO:0002102), cytosol (GO:0005829), focal adhesion (GO:0005925), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell surface (GO:0009986), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
MET promotes cell motility	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by MET	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
phosphate-containing compound metabolic process	1
phosphatase activity	1
catalytic activity, acting on a protein	1
cytoskeletal protein binding	1
binding	1
transition metal ion binding	1
catalytic activity	1
cation binding	1
actin-based cell projection	1
cytoplasm	1
cell-substrate junction	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
cell junction	1

Protein interactions and networks

STRING

1682 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNS3	BCAR1	P56945	816
TNS3	ITGB1	P05556	741
TNS3	SRC	P12931	732
TNS3	PXN	P49023	660
TNS3	VCL	P18206	619
TNS3	EGFR	P00533	612
TNS3	PTK2	Q05397	564
TNS3	STARD8	Q92502	555
TNS3	ERBB2	P04626	535
TNS3	EGF	P01133	532
TNS3	DLC1	Q96QB1	511
TNS3	SHC1	P29353	472
TNS3	EXOC6B	Q9Y2D4	467
TNS3	PSEN1	P49768	450
TNS3	GLDC	P23378	446

IntAct

86 interactions, top by confidence:

A	B	Type	Score
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EGFR	TNS3	psi-mi:“MI:0915”(physical association)	0.680
TNS3	EGFR	psi-mi:“MI:0915”(physical association)	0.680
CSK	TNS3	psi-mi:“MI:0914”(association)	0.640
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
SRC	TNS3	psi-mi:“MI:0915”(physical association)	0.590
TNS3	SRC	psi-mi:“MI:0915”(physical association)	0.590
SRC	TNS3	psi-mi:“MI:0914”(association)	0.590
TNS3	SRC	psi-mi:“MI:0217”(phosphorylation reaction)	0.590
TNS3	PTK2	psi-mi:“MI:0403”(colocalization)	0.560
TNS3	BCAR1	psi-mi:“MI:0403”(colocalization)	0.560
TNS3	BCAR1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (103): TNS3 (Affinity Capture-RNA), TNS3 (Affinity Capture-RNA), TNS3 (Affinity Capture-RNA), TNS3 (Two-hybrid), TNS3 (Biochemical Activity), TNS3 (Affinity Capture-MS), TNS3 (PCA), TNS3 (Affinity Capture-Luminescence), CTNNAL1 (Affinity Capture-MS), DMD (Affinity Capture-MS), DTNB (Affinity Capture-MS), PYCR2 (Affinity Capture-MS), SNTB1 (Affinity Capture-MS), SNTB2 (Affinity Capture-MS), UTRN (Affinity Capture-MS)

ESM2 similar proteins: A0JPN4, A2A288, A2ARK0, A6ND36, A6QQJ8, A7E316, E9Q0S6, E9Q2Z1, O15037, O54714, O54967, O70260, O70405, O75385, O94983, P42335, P48778, Q07912, Q0P4K8, Q17R13, Q1LVK9, Q32PJ7, Q4V8I3, Q5D1E7, Q5D1E8, Q5DTV4, Q5HYM0, Q5JV73, Q5SWY7, Q5SXM2, Q5U2X5, Q5XIS1, Q68CZ2, Q6A037, Q6IRU7, Q6P1H6, Q6S5L8, Q7TP65, Q7TSG2, Q80U38

Diamond homologs: E9Q0S6, G5EE01, H2L045, O08586, O14976, O54857, P60483, P60484, P97874, Q04205, Q32PJ7, Q4R6N0, Q4V8I3, Q54JL7, Q5SSZ5, Q63HR2, Q68CZ2, Q6NR09, Q8BZ33, Q8CGB6, Q8H106, Q8IZW8, Q8T9S7, Q99KY4, Q9FLZ5, Q9GLM4, Q9HBL0, Q9LT75, Q9PUT6, O94526, P56180, Q9P7H1, Q5B323, Q6XPS3, Q86IL4, O75061, Q27974, Q5F4C0, Q80TZ3, Q96D96

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	TNS3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	76.0×	2e-08
Activation of BAD and translocation to mitochondria	5	71.8×	9e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	63.4×	1e-06
Activation of BH3-only proteins	5	46.8×	4e-06
Integrin signaling	5	39.9×	7e-06
RHO GTPases activate PKNs	6	35.9×	1e-06
Intrinsic Pathway for Apoptosis	5	27.6×	3e-05
Constitutive Signaling by Aberrant PI3K in Cancer	8	19.1×	9e-07

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	9	37.2×	2e-09
cell surface receptor protein tyrosine kinase signaling pathway	5	14.5×	2e-03
integrin-mediated signaling pathway	5	13.4×	3e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	10.4×	3e-04
intracellular signal transduction	9	5.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	214
Likely benign	32
Benign	19

Top pathogenic / likely-pathogenic (0)

SpliceAI

7397 predictions. Top by Δscore:

Variant	Effect	Δscore
7:47278219:CT:C	acceptor_gain	1.0000
7:47280162:A:AC	donor_gain	1.0000
7:47280163:C:CC	donor_gain	1.0000
7:47280188:CACCT:C	acceptor_gain	1.0000
7:47280192:T:C	acceptor_gain	1.0000
7:47280192:T:TC	acceptor_gain	1.0000
7:47280199:T:C	acceptor_gain	1.0000
7:47280199:T:TC	acceptor_gain	1.0000
7:47280284:A:AC	donor_gain	1.0000
7:47280284:ACTT:A	donor_gain	1.0000
7:47280285:C:CA	donor_gain	1.0000
7:47280285:CTT:C	donor_gain	1.0000
7:47280285:CTTC:C	donor_gain	1.0000
7:47280287:T:TA	donor_gain	1.0000
7:47280288:C:A	donor_gain	1.0000
7:47283690:CACT:C	donor_loss	1.0000
7:47283691:ACTC:A	donor_loss	1.0000
7:47283693:TCA:T	donor_loss	1.0000
7:47283694:CACTT:C	donor_loss	1.0000
7:47283695:A:AC	donor_gain	1.0000
7:47283695:ACTT:A	donor_gain	1.0000
7:47283695:ACTTC:A	donor_gain	1.0000
7:47283696:C:CA	donor_gain	1.0000
7:47283696:C:G	donor_loss	1.0000
7:47283696:CTT:C	donor_gain	1.0000
7:47283696:CTTC:C	donor_gain	1.0000
7:47283696:CTTCC:C	donor_gain	1.0000
7:47283698:T:TA	donor_gain	1.0000
7:47283861:GCAGG:G	acceptor_gain	1.0000
7:47283862:CAGG:C	acceptor_gain	1.0000

AlphaMissense

9453 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:47278209:A:G	F1402S	1.000
7:47278212:C:T	G1401E	1.000
7:47283715:A:G	L1360P	1.000
7:47297132:G:T	A1209D	1.000
7:47297135:A:G	L1208P	1.000
7:47297138:C:T	G1207D	1.000
7:47297168:C:G	R1197P	1.000
7:47297171:A:T	V1196D	1.000
7:47368541:A:G	L702P	1.000
7:47278113:A:T	V1434E	0.999
7:47278115:G:C	F1433L	0.999
7:47278115:G:T	F1433L	0.999
7:47278116:A:G	F1433S	0.999
7:47278117:A:G	F1433L	0.999
7:47278122:A:T	V1431D	0.999
7:47278125:A:T	I1430N	0.999
7:47278161:A:G	F1418S	0.999
7:47278164:A:G	L1417P	0.999
7:47278203:G:T	A1404D	0.999
7:47278208:A:C	F1402L	0.999
7:47278208:A:T	F1402L	0.999
7:47278210:A:G	F1402L	0.999
7:47278213:C:G	G1401R	0.999
7:47278213:C:T	G1401R	0.999
7:47280311:A:G	C1381R	0.999
7:47283699:C:A	R1365S	0.999
7:47283699:C:G	R1365S	0.999
7:47283715:A:T	L1360Q	0.999
7:47283725:C:G	G1357R	0.999
7:47283742:A:G	F1351S	0.999

dbSNP variants (sampled 300 via entrez): RS1000010611 (7:47355665 G>A), RS1000017356 (7:47308944 T>C), RS1000021287 (7:47474075 T>C), RS1000026133 (7:47470675 G>A,C,T), RS1000057096 (7:47351304 G>A), RS1000064315 (7:47275062 A>G,T), RS1000073545 (7:47511947 C>A,T), RS1000091856 (7:47430272 G>C), RS1000123272 (7:47356036 C>G,T), RS1000149818 (7:47394139 A>T), RS1000163206 (7:47394388 G>A), RS1000168181 (7:47535504 G>C), RS1000176019 (7:47437957 G>A), RS1000190116 (7:47355610 C>T), RS1000193266 (7:47479589 C>T)

Disease associations

OMIM: gene MIM:606825 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

59 associations (top):

Study	Trait	p-value
GCST000937_6	Insulin-like growth factors	4.000000e-21
GCST000937_7	Insulin-like growth factors	5.000000e-09
GCST002415_11	Colorectal cancer (diet interaction)	2.000000e-06
GCST002606_14	Prostate cancer	2.000000e-09
GCST002606_33	Prostate cancer	9.000000e-09
GCST002709_2	Electroencephalogram traits	6.000000e-06
GCST002937_11	Molybdenum levels	6.000000e-06
GCST002949_6	Epilepsy and lamotrigine-induced maculopapular eruptions	5.000000e-07
GCST003726_29	Basal cell carcinoma	4.000000e-08
GCST003844_1	QRS duration	5.000000e-09
GCST003983_36	Male-pattern baldness	3.000000e-09
GCST004029_14	Angiotensin-converting enzyme inhibitor intolerance	1.000000e-06
GCST004611_75	High light scatter reticulocyte count	4.000000e-09
GCST004612_34	High light scatter reticulocyte percentage of red cells	3.000000e-09
GCST004613_110	Sum neutrophil eosinophil counts	7.000000e-09
GCST004614_102	Granulocyte count	4.000000e-09
GCST004620_75	Sum basophil neutrophil counts	4.000000e-09
GCST004626_104	Myeloid white cell count	9.000000e-10
GCST004628_91	Immature fraction of reticulocytes	5.000000e-13
GCST004629_116	Neutrophil count	7.000000e-09
GCST005434_2	Pancreatic cancer	1.000000e-07
GCST005440_13	Alcohol dependence symptom count	1.000000e-06
GCST005757_10	Dimensional psychopathology (Positive)	4.000000e-06
GCST006009_5	Pulse pressure	2.000000e-08
GCST006626_6	Pulse pressure	7.000000e-13
GCST007094_153	Diastolic blood pressure	4.000000e-12
GCST007094_171	Diastolic blood pressure	6.000000e-14
GCST007096_165	Pulse pressure	9.000000e-50
GCST007096_46	Pulse pressure	2.000000e-49
GCST007097_33	Pulse pressure	8.000000e-17

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0004626	IGFBP-3 measurement
EFO:0004627	IGF-1 measurement
EFO:0008111	diet measurement
EFO:0004357	electroencephalogram measurement
EFO:0006870	alpha wave measurement
EFO:1001253	maculopapular eruption
EFO:0005054	QRS complex
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0007986	reticulocyte count
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0007835	alcohol dependence measurement
EFO:0009097	positive domain measurement
EFO:0005763	pulse pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0009764	eye colour measurement
EFO:0004344	birth weight
EFO:0010176	keratinocyte carcinoma
EFO:0007936	disease prognosis measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295861 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	5
Tetrachlorodibenzodioxin	increases expression, affects cotreatment	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Tretinoin	increases expression	3
bisphenol A	affects expression, affects methylation, affects cotreatment, increases methylation	2
trichostatin A	increases expression, affects expression	2
methacrylaldehyde	increases abundance, affects cotreatment, increases expression	2
(+)-JQ1 compound	decreases expression	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Air Pollutants	increases abundance, increases expression, decreases expression, affects cotreatment	2
Arsenic	increases abundance, increases expression, affects cotreatment, decreases expression	2
Cisplatin	decreases expression	2
Ozone	increases abundance, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Raloxifene Hydrochloride	affects cotreatment, decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
deoxynivalenol	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118977	Binding	Binding affinity to TNS3 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1584	NCI-H727	Cancer cell line	Female

Clinical trials (associated diseases)

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