TNS4

Summary

TNS4 (tensin 4, HGNC:24352) is a protein-coding gene on chromosome 17q21.2, encoding Tensin-4 (Q8IZW8). Promotes EGF-induced cell migration by displacing tensin TNS3 from the cytoplasmic tail of integrin ITGB1 which results in dissociation of TNS3 from focal adhesions, disassembly of actin stress fibers and initiation of cell migration.

Predicted to enable actin binding activity. Involved in protein localization. Located in cytosol and focal adhesion.

Source: NCBI Gene 84951 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 131 total
• Druggable target: yes
• MANE Select transcript: NM_032865

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24352
Approved symbol	TNS4
Name	tensin 4
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	CTEN
Ensembl gene	ENSG00000131746
Ensembl biotype	protein_coding
OMIM	608385
Entrez	84951

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000254051, ENST00000394072, ENST00000497303, ENST00000582747, ENST00000876606

RefSeq mRNA: 1 — MANE Select: NM_032865 NM_032865

CCDS: CCDS11368

Canonical transcript exons

ENST00000254051 — 13 exons

Exon	Start	End
ENSE00000720646	40482129	40482206
ENSE00000720719	40482324	40482416
ENSE00000863408	40484484	40484609
ENSE00000900633	40479674	40479842
ENSE00000900634	40480700	40480768
ENSE00000900635	40484921	40485007
ENSE00000900636	40487036	40487460
ENSE00001177363	40488546	40488969
ENSE00001229785	40495987	40496520
ENSE00001433415	40501534	40501623
ENSE00003465953	40478580	40478648
ENSE00003481478	40478307	40478333
ENSE00003618679	40475834	40477729

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 98.59.

FANTOM5 (CAGE): breadth broad, TPM avg 30.3818 / max 2441.4051, expressed in 412 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165753	30.0968	412
165747	0.1043	54
165750	0.0600	40
165749	0.0472	18
165752	0.0299	14
165745	0.0234	11
165748	0.0202	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	98.59	gold quality
skin of leg	UBERON:0001511	97.96	gold quality
zone of skin	UBERON:0000014	96.02	gold quality
minor salivary gland	UBERON:0001830	95.17	gold quality
mouth mucosa	UBERON:0003729	93.96	gold quality
lower esophagus mucosa	UBERON:0035834	93.94	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.81	gold quality
esophagus mucosa	UBERON:0002469	92.70	gold quality
saliva-secreting gland	UBERON:0001044	92.69	gold quality
gingival epithelium	UBERON:0001949	91.31	silver quality
mucosa of paranasal sinus	UBERON:0005030	90.94	gold quality
mammary duct	UBERON:0001765	90.85	gold quality
gingiva	UBERON:0001828	90.31	gold quality
nipple	UBERON:0002030	88.78	gold quality
epithelium of mammary gland	UBERON:0003244	88.41	gold quality
vagina	UBERON:0000996	88.04	gold quality
upper leg skin	UBERON:0004262	87.09	gold quality
tonsil	UBERON:0002372	85.76	gold quality
oral cavity	UBERON:0000167	85.51	gold quality
upper arm skin	UBERON:0004263	84.91	gold quality
prostate gland	UBERON:0002367	84.15	gold quality
mammalian vulva	UBERON:0000997	84.10	gold quality
epithelium of nasopharynx	UBERON:0001951	83.33	silver quality
mucosa of transverse colon	UBERON:0004991	83.01	gold quality
placenta	UBERON:0001987	82.82	gold quality
penis	UBERON:0000989	81.82	gold quality
nasal cavity mucosa	UBERON:0001826	81.74	gold quality
left lobe of thyroid gland	UBERON:0001120	81.16	gold quality
right lobe of thyroid gland	UBERON:0001119	81.00	gold quality
skin of hip	UBERON:0001554	80.59	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	58.58
E-CURD-11	no	67.63
E-MTAB-8060	no	51.96
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

90 targeting TNS4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-92A-2-5P	99.75	67.01	2164

Literature-anchored findings (GeneRIF, showing 38)

• Increased cten mRNA expression was correlated with tumor progression in lung cancers (PMID:12711115)
• Cten/GAPDH mRNA expression was correlated with evidence of tumor progression in thymoma. (PMID:15001839)
• These results provide a novel mechanism whereby the SH2 domain of cten-mediated focal adhesion localization of DLC-1 plays an essential role in its tumor suppression activity. (PMID:17190795)
• Data show that EGF downregulates tensin-3 expression, and concomitantly upregulates cten, a tensin family member that lacks the actin-binding domain. (PMID:17643115)
• Expression of CTEN correlates with high tumor grade and metastasis to lymph nodes, suggesting that CTEN may contribute to tumor invasiveness. (PMID:17765673)
• TNS4 mRNA expression was significantly higher in gastric cancer. (PMID:18612693)
• 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)
• Cten is a novel nuclear partner of beta-catenin, and has an oncogenic activity in colon cancers. (PMID:19487278)
• CTEN plays an important role in paclitaxel sensitivity, and CTEN expression level may be a prognostic predictive factor for prostate cancer patients. (PMID:19725034)
• CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma. (PMID:20390342)
• Cten expression is of prognostic significance in colorectal carcinoma, and delineate a Cten-ILK pathway controlling cell motility and possibly promoting metastasis. (PMID:21339732)
• conclude that, in the colon and pancreas, Cten is a downstream target of Kras and may be a mechanism through which Kras regulates of cell motility (PMID:21698197)
• Show an oncogenic role for CTEN in pancreatic cancer through promotion of colony formation and cell motility. (PMID:22750970)
• Phylogenetic analysis, expression patterns, and transcriptional regulation of human CTEN gene. (PMID:23500447)
• Up-regulated cten modulates cell migration induced by FGF2. (PMID:23625726)
• CTEN regulates EGFR protein levels through a posttranslational mechanism. (PMID:23774213)
• Findings indicate that induction of Cten protein expression is a relatively early event in melanoma progression, and that Cten has the potential to serve as a prognostic marker for primary melanoma patients. (PMID:24244691)
• Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer. (PMID:24814316)
• Cten expression mediates invasion of human lung cancer cells and is upregulated by epidermal growth factor via STAT3. (PMID:25439778)
• Tensin4 is up-regulated by EGF-induced ERK1/2 activity and promotes cell proliferation and migration in hepatocellular carcinoma (PMID:26035355)
• Conclude that in colorectal cancer, Cten is upregulated by EGFR and Kras but downregulated by STAT3. (PMID:26852686)
• Cten-Snail signaling pathway contributes to cell motility in colorectal cancer (CRC), mediated by the stabilization of Snail protein. (PMID:28691764)
• Overexpression of the TNS4 gene is a useful independent predictor of outcomes in patients with stage II/III gastric cancer who undergo surgery and receive adjuvant chemotherapy with S-1. (PMID:29102927)
• CTEN activated the expression of TGFB1, thereby prompting epithelial-mesenchymal transition in lung adenocarcinoma cancer cells. (PMID:29985912)
• Results suggest that nuclear Cten contributes to cancer cell proliferation. Findings identify a molecular mechanism for regulating Cten protein trafficking in mammalian cells and provide new insights into the dynamics of focal adhesion complexes in health and disease. (PMID:30321615)
• induction of CTEN reactivates focal adhesion kinase (FAK) Y(397) phosphorylation and disrupts the acini structure. (PMID:30332774)
• Cten may play an essential role in mediating TGF-beta1-induced EMT and cell motility and may therefore play a role in metastasis in colorectal cancer. (PMID:30648319)
• Src is a novel and functionally important target of the Cten signaling pathway and that Cten protein causes post-transcriptional stabilization of Src in promoting EMT and possibly metastasis in colorectal cancer (PMID:31290243)
• The authors propose that TNS4 plays a crucial role in CRC tumorigenesis, and that suppression of TNS4 would be an effective therapeutic strategy in treating a subset of cetuximab-refractory CRC patients including KRAS activating mutations. (PMID:31409052)
• analysis of cten force-induced recruitment along keratin network in epithelial cells (PMID:31527270)
• Investigating TNS4 in the Colorectal Tumor Microenvironment Using 3D Spheroid Models of Invasion. (PMID:32390347)
• Tensin4 promotes invasion and migration of gastric cancer cells via regulating AKT/GSK-3beta/snail signaling pathway. (PMID:32534709)
• Histone acetyltransferase p300 mediates the upregulation of CTEN induced by the activation of EGFR signaling in cancer cells. (PMID:33310188)
• CTEN Inhibits Tumor Angiogenesis and Growth by Targeting VEGFA Through Down-Regulation of beta-Catenin in Breast Cancer. (PMID:34817293)
• Mining TCGA and GEO databases for the prediction of poor prognosis in lung adenocarcinoma based on up-regulated expression of TNS4. (PMID:36281194)
• Nuclear-localized CTEN is a novel transcriptional regulator and promotes cancer cell migration through its downstream target CDC27. (PMID:36399312)
• Epigenetic Activation of Tensin 4 Promotes Gastric Cancer Progression. (PMID:36896596)
• GPRC5A promotes gallbladder cancer metastasis by upregulating TNS4 via the JAK2-STAT3 pathway. (PMID:38942137)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tns4	ENSMUSG00000017607
rattus_norvegicus	Tns4	ENSRNOG00000027350
drosophila_melanogaster	PVRAP	FBGN0052406
drosophila_melanogaster	Egfrap	FBGN0053993
caenorhabditis_elegans		WBGENE00020867

Paralogs (1): TNS2 (ENSG00000111077)

Protein

Protein identifiers

Tensin-4 — Q8IZW8 (reviewed: Q8IZW8)

Alternative names: C-terminal tensin-like protein

All UniProt accessions (2): J3QLA4, Q8IZW8

UniProt curated annotations — full annotation on UniProt →

Function. Promotes EGF-induced cell migration by displacing tensin TNS3 from the cytoplasmic tail of integrin ITGB1 which results in dissociation of TNS3 from focal adhesions, disassembly of actin stress fibers and initiation of cell migration. Suppresses ligand-induced degradation of EGFR by reducing EGFR ubiquitination in the presence of EGF. Increases MET protein stability by inhibiting MET endocytosis and subsequent lysosomal degradation which leads to increased cell survival, proliferation and migration.

Subunit / interactions. Interacts (via SH2 domain) with Rho GTPase-activating protein DLC1 (via C-terminus); the interaction is independent of DLC1 tyrosine phosphorylation. Interacts with integrin ITGB1; the interaction displaces tensin TNS3 from the ITGB1 cytoplasmic tail and promotes ITGB1 stability. Interacts (via SH2 domain) with E3 ubiquitin-protein ligase CBL (phosphorylated on ‘Tyr-774’); the interaction is enhanced in the presence of EGF and reduces interaction of CBL with EGFR. Interacts (via SH2 domain) with receptor tyrosine kinase MET (when phosphorylated); the interaction increases MET protein stability.

Subcellular location. Cell junction. Focal adhesion. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed at low levels in colon (at protein level). Expressed in prostate and placenta.

Post-translational modifications. Proteolytically cleaved by caspase-3 during apoptosis.

Induction. By EGF.

Miscellaneous. Expression is up-regulated in tumors from a variety of tissues including lung, breast, colon, pancreas, stomach and ovary but is down-regulated in prostate cancer. In colorectal cancer cells, induces epithelial-mesenchymal transition (EMT) accompanied by down-regulation of CDH1/E-cadherin protein levels and increased cell migration. Contributes to cell motility in colorectal cancer cells by promoting EMT through its role in the post-transcriptional stabilization of SNAIL in an SH2-dependent manner which leads to increased cell migration. Detected in the nucleus in colon cancer cells where it interacts with CTNNB1/beta-catenin and modulates colony formation, anchorage-independent growth and cell invasiveness. Also detected in the nucleus in other cancer cells such as lung and cervical cancer cells where it promotes cell proliferation.

Similarity. Belongs to the PTEN phosphatase protein family.

RefSeq proteins (1): NP_116254* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013625	PTB	Domain
IPR033929	Tensin_PTB	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051484	Tensin_PTEN_phosphatase	Family

Pfam: PF00017, PF08416

UniProt features (25 total): mutagenesis site 5, sequence variant 4, region of interest 4, sequence conflict 3, modified residue 2, domain 2, compositionally biased region 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZW8-F1	60.26	0.29

Functional residue map

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

Catalytic / active sites (1): 570–571 (cleavage; by caspase-3)

Post-translational modifications (2): 82, 248

Mutagenesis-validated functional residues (5):

Position	Phenotype
100–118	abolishes focal adhesion localization; when associated with a-474.
474	abolishes interaction with dlc1. abolishes interaction with cbl following egf stimulation. loss of ability to reduce ubi
506	no effect on cleavage by caspase-3.
570	abolishes cleavage by caspase-3.
650	abolishes interaction with itgb1. does not affect interaction with cbl following egf stimulation.

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: 95 (showing top): RODRIGUES_NTN1_TARGETS_DN, BILD_HRAS_ONCOGENIC_SIGNATURE, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOMF_ACTIN_BINDING, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP, GOCC_ANCHORING_JUNCTION, NUYTTEN_NIPP1_TARGETS_DN, GOMF_CYTOSKELETAL_PROTEIN_BINDING, JI_METASTASIS_REPRESSED_BY_STK11, LIU_PROSTATE_CANCER_DN, MIKKELSEN_MCV6_LCP_WITH_H3K4ME3, FORTSCHEGGER_PHF8_TARGETS_DN, LIM_MAMMARY_STEM_CELL_UP, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY

GO Biological Process (1): intracellular protein localization (GO:0008104)

GO Molecular Function (2): actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (5): cytosol (GO:0005829), cytoskeleton (GO:0005856), focal adhesion (GO:0005925), cytoplasm (GO:0005737), 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	2
macromolecule localization	1
cytoskeletal protein binding	1
binding	1
cytoplasm	1
intracellular membraneless organelle	1
cell-substrate junction	1
intracellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1032 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNS4	BCAR1	P56945	798
TNS4	PTK2	Q05397	739
TNS4	SRC	P12931	729
TNS4	DLC1	Q96QB1	621
TNS4	VCL	P18206	606
TNS4	PXN	P49023	604
TNS4	PTEN	P60484	593
TNS4	ITGB1	P05556	529
TNS4	STARD8	Q92502	529
TNS4	CTNNB1	P35222	523
TNS4	ERBB2	P04626	502
TNS4	EGF	P01133	469
TNS4	SMIM10L1	P0DMW3	432
TNS4	LATS2	Q9NRM7	430
TNS4	TIMP3	P35625	421

IntAct

62 interactions, top by confidence:

A	B	Type	Score
TNS4	EGFR	psi-mi:“MI:0407”(direct interaction)	0.590
TNS4	CARD9	psi-mi:“MI:0915”(physical association)	0.560
TXK	TNS4	psi-mi:“MI:0915”(physical association)	0.560
TRIM27	TNS4	psi-mi:“MI:0915”(physical association)	0.560
TRIM21	TNS4	psi-mi:“MI:0915”(physical association)	0.560
RABEP1	TNS4	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	TNS4	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	TNS4	psi-mi:“MI:0915”(physical association)	0.560
TNS4	ZRANB1	psi-mi:“MI:0915”(physical association)	0.560
PPP3CA	TNS4	psi-mi:“MI:0915”(physical association)	0.560
KAZN	TNS4	psi-mi:“MI:0915”(physical association)	0.560
TNS4	PIH1D1	psi-mi:“MI:0915”(physical association)	0.560
TNS4	P4HA2	psi-mi:“MI:0915”(physical association)	0.490
TNS4	GSTCD	psi-mi:“MI:0915”(physical association)	0.490
TNS4	RPAIN	psi-mi:“MI:0915”(physical association)	0.490
PIK3R1	TNS4	psi-mi:“MI:0915”(physical association)	0.490
TNS4	NME4	psi-mi:“MI:0915”(physical association)	0.490
P4HA2	TNS4	psi-mi:“MI:0915”(physical association)	0.490
GSTCD	TNS4	psi-mi:“MI:0915”(physical association)	0.490
NME4	TNS4	psi-mi:“MI:0915”(physical association)	0.490
TNS4	PIK3R1	psi-mi:“MI:0915”(physical association)	0.490
RPAIN	TNS4	psi-mi:“MI:0915”(physical association)	0.490
TNS4	ERBB3	psi-mi:“MI:0407”(direct interaction)	0.440
TNS4	AR	psi-mi:“MI:0407”(direct interaction)	0.440
TNS4	GAB1	psi-mi:“MI:0407”(direct interaction)	0.440
TNS4	MET	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (46): GSTCD (Two-hybrid), NME4 (Two-hybrid), P4HA2 (Two-hybrid), PIK3R1 (Two-hybrid), RPAIN (Two-hybrid), KCTD4 (Two-hybrid), TNS4 (Affinity Capture-MS), TNS4 (PCA), TNS4 (Affinity Capture-MS), TNS4 (Two-hybrid), TNS4 (Two-hybrid), TNS4 (Two-hybrid), TNS4 (Two-hybrid), TRIM21 (Two-hybrid), PPP3CA (Two-hybrid)

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, G5ECJ6, O94526, A6QLK6, P00519, P00520, P00521, P00522, P10447, P42684, P42686, P62993

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Constitutive Signaling by Aberrant PI3K in Cancer	6	30.4×	6e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	23.2×	1e-05
PIP3 activates AKT signaling	6	16.0×	6e-05
RAF/MAP kinase cascade	5	12.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	103
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2203 predictions. Top by Δscore:

Variant	Effect	Δscore
17:40478578:A:AC	donor_gain	1.0000
17:40478579:C:CC	donor_gain	1.0000
17:40478581:T:TA	donor_gain	1.0000
17:40478645:CACC:C	acceptor_gain	1.0000
17:40478646:ACCCT:A	acceptor_loss	1.0000
17:40478647:CC:C	acceptor_gain	1.0000
17:40478648:CC:C	acceptor_gain	1.0000
17:40478648:CCT:C	acceptor_loss	1.0000
17:40478649:C:A	acceptor_loss	1.0000
17:40478650:T:A	acceptor_loss	1.0000
17:40479672:A:AC	donor_gain	1.0000
17:40479672:ACTT:A	donor_gain	1.0000
17:40479673:C:CC	donor_gain	1.0000
17:40479673:CTT:C	donor_gain	1.0000
17:40479673:CTTC:C	donor_gain	1.0000
17:40479675:T:TA	donor_gain	1.0000
17:40479676:C:A	donor_gain	1.0000
17:40482205:CC:C	acceptor_gain	1.0000
17:40482206:CC:C	acceptor_gain	1.0000
17:40482318:TCTCA:T	donor_loss	1.0000
17:40482319:CTCA:C	donor_loss	1.0000
17:40482320:TCAC:T	donor_loss	1.0000
17:40482321:CA:C	donor_loss	1.0000
17:40482322:A:AC	donor_gain	1.0000
17:40482323:C:CC	donor_gain	1.0000
17:40482323:C:CT	donor_loss	1.0000
17:40482341:T:C	donor_gain	1.0000
17:40482412:CTCAC:C	acceptor_gain	1.0000
17:40482413:TCAC:T	acceptor_gain	1.0000
17:40482414:CAC:C	acceptor_gain	1.0000

AlphaMissense

4643 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:40479692:A:G	L631P	0.998
17:40479725:A:T	V620D	0.998
17:40484951:A:G	W449R	0.998
17:40484951:A:T	W449R	0.998
17:40477721:C:T	G672E	0.997
17:40478332:A:G	W661R	0.997
17:40478332:A:T	W661R	0.997
17:40478634:C:G	R642P	0.997
17:40479677:C:G	R636T	0.997
17:40484531:A:G	L485P	0.997
17:40484572:A:C	F471L	0.997
17:40484572:A:T	F471L	0.997
17:40484574:A:G	F471L	0.997
17:40478639:G:C	F640L	0.996
17:40478639:G:T	F640L	0.996
17:40478641:A:G	F640L	0.996
17:40479676:C:A	R636S	0.996
17:40479676:C:G	R636S	0.996
17:40482325:A:C	F531L	0.996
17:40482325:A:T	F531L	0.996
17:40482327:A:G	F531L	0.996
17:40484525:A:G	L487P	0.996
17:40484557:G:C	S476R	0.996
17:40484557:G:T	S476R	0.996
17:40484559:T:G	S476R	0.996
17:40484946:A:C	F450L	0.996
17:40484946:A:T	F450L	0.996
17:40484948:A:G	F450L	0.996
17:40484973:G:C	F441L	0.996
17:40484973:G:T	F441L	0.996

dbSNP variants (sampled 300 via entrez): RS1000088593 (17:40484742 C>A,T), RS1000120401 (17:40491046 A>C), RS1000361422 (17:40479383 G>A), RS1000708779 (17:40475349 T>C), RS1000979430 (17:40480962 T>C), RS1000986082 (17:40490708 C>T), RS1001154905 (17:40496703 T>A), RS1001210224 (17:40498258 T>C), RS1001291620 (17:40492482 C>G,T), RS1001353435 (17:40491149 C>T), RS1001491254 (17:40498048 T>C), RS1001560749 (17:40498848 C>T), RS1001562804 (17:40502766 C>T), RS1001621535 (17:40485967 T>C), RS1001721584 (17:40492243 C>T)

Disease associations

OMIM: gene MIM:608385 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005434_31	Pancreatic cancer	1.000000e-06
GCST007235_7	Pancreatic ductal adenocarcinoma	7.000000e-06
GCST009798_47	Asthma	3.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067432 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.11	Kd	7692	nM	CHEMBL5653589
5.06	ED50	8672	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149630: Binding affinity to human TNS4 incubated for 45 mins by Kinobead based pull down assay	kd	7.6924	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, decreases methylation, increases expression	4
Estradiol	affects expression, affects cotreatment, increases expression	3
Air Pollutants	increases expression, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Lipopolysaccharides	affects expression, affects response to substance, affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
fluorene-9-bisphenol	increases expression	1
propionaldehyde	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
pentanal	increases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	decreases expression	1
azaspiracid	increases expression	1
abrine	decreases expression	1
ormosil	affects binding, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Aldehydes	increases expression	1
Atrazine	increases expression	1
Calcitriol	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Furaldehyde	affects cotreatment, affects localization, 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
CHEMBL5652672	Binding	Binding affinity to human TNS4 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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