TNFSF9

Summary

TNFSF9 (TNF superfamily member 9, HGNC:11939) is a protein-coding gene on chromosome 19p13.3, encoding Tumor necrosis factor ligand superfamily member 9 (P41273). Cytokine that binds to TNFRSF9.

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This transmembrane cytokine is a bidirectional signal transducer that acts as a ligand for TNFRSF9/4-1BB, which is a costimulatory receptor molecule in T lymphocytes. This cytokine and its receptor are involved in the antigen presentation process and in the generation of cytotoxic T cells. The receptor TNFRSF9/4-1BB is absent from resting T lymphocytes but rapidly expressed upon antigenic stimulation. The ligand encoded by this gene, TNFSF9/4-1BBL, has been shown to reactivate anergic T lymphocytes in addition to promoting T lymphocyte proliferation. This cytokine has also been shown to be required for the optimal CD8 responses in CD8 T cells. This cytokine is expressed in carcinoma cell lines, and is thought to be involved in T cell-tumor cell interaction.

Source: NCBI Gene 8744 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary predisposition to infections (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 31 total
• MANE Select transcript: NM_003811

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11939
Approved symbol	TNFSF9
Name	TNF superfamily member 9
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	4-1BB-L, 4-1BBL, CD137L
Ensembl gene	ENSG00000125657
Ensembl biotype	protein_coding
OMIM	606182
Entrez	8744

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000245817

RefSeq mRNA: 1 — MANE Select: NM_003811 NM_003811

CCDS: CCDS12169

Canonical transcript exons

ENST00000245817 — 3 exons

Exon	Start	End
ENSE00001053499	6532786	6532816
ENSE00001159913	6531026	6531303
ENSE00001243732	6534600	6535924

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 87.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.3489 / max 4499.6119, expressed in 1579 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173487	30.3489	1579

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	87.99	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.97	gold quality
lower esophagus mucosa	UBERON:0035834	77.26	gold quality
esophagus mucosa	UBERON:0002469	74.97	gold quality
medial globus pallidus	UBERON:0002477	71.52	silver quality
endothelial cell	CL:0000115	70.36	gold quality
vagina	UBERON:0000996	69.70	gold quality
endometrium epithelium	UBERON:0004811	69.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	69.00	gold quality
cervix squamous epithelium	UBERON:0006922	68.86	silver quality
right frontal lobe	UBERON:0002810	68.50	gold quality
upper lobe of left lung	UBERON:0008952	68.31	gold quality
prefrontal cortex	UBERON:0000451	68.13	gold quality
hindlimb stylopod muscle	UBERON:0004252	67.62	gold quality
cerebellar hemisphere	UBERON:0002245	67.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	67.55	gold quality
cerebellar cortex	UBERON:0002129	67.50	gold quality
upper lobe of lung	UBERON:0008948	67.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	67.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	67.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.97	gold quality
cingulate cortex	UBERON:0003027	66.71	gold quality
anterior cingulate cortex	UBERON:0009835	66.43	gold quality
hypothalamus	UBERON:0001898	66.42	gold quality
epithelium of esophagus	UBERON:0001976	66.14	silver quality
cartilage tissue	UBERON:0002418	66.14	silver quality
cerebellum	UBERON:0002037	66.06	gold quality
frontal cortex	UBERON:0001870	66.01	gold quality
olfactory bulb	UBERON:0002264	65.84	gold quality
neocortex	UBERON:0001950	65.42	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	161.56
E-MTAB-8060	no	256.57
E-ANND-3	no	2.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

75 targeting TNFSF9, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6780A-5P	99.88	66.69	2776

Literature-anchored findings (GeneRIF, showing 40)

• 4-1BBL provides a costimulatory signal for T cell activation, thereby allowing T cell expansion as well as cytokine production and the development of cytolytic effector function. (PMID:11994439)
• Stimulation of 4-1BBL on DCs with 4-1BB-Fc or with 4-1BB-transfected Jurkat cells resulted in acquisition of capacity for the immature DCs to produce IL-12, suggesting that 4-1BBL may be an important mediator for maturation of CD11c(+) myeloid DCs (PMID:12590704)
• 4-1 BB ligand can costimulate human CD28- T cells, resulting in cell division, inflammatory cytokine production, increased perforin levels, enhancement of cytolytic effector function, as well as the up-regulation of the anti-apoptotic protein Bcl-X(L). (PMID:12645943)
• First evidence of expression and synthesis of CD137 and its ligand by human brain cells. (PMID:13130507)
• Data show that reverse signaling via 4-1BB-ligand enhanced interleukin-12beta mRNA and the secretion of IL-12 p70 in various antigen-presenting cells, including monocytes. (PMID:14746806)
• 4-1BB/4-1BBL and Fas/FasL pathways play important roles in vascular injury in Takayasu’s arteritis. (PMID:14752253)
• Data suggest that levels of soluble 4-1BB and 4-1BB ligand in sera at the time of diagnosis may be indicative of the severity and outcome of rheumatoid arthritis. (PMID:15031666)
• trimeric CD137L (4-1BBL) requires cross-linking for its T cell co-stimulation activity (PMID:16204238)
• Signaling through 4-1BB-L allows B cells to proliferate and the expression of its ligand, by the intra-tumoral mesh of follicular dendritic cells (FDC), could thus serve as a paracrine loop facilitating growth and survival of MCL cells (PMID:16287062)
• Significantly lower CD137 ligand is associated with colorectal cancer patients (PMID:16596186)
• Elevated plasma levels of 4-1BBL in multiple sclerosis patients may function as a self-regulatory mechanism of the 4-1BB/4-1BBL pathway involved in the disease process. (PMID:16970683)
• Here we document a function for the TNF family member 4-1BB ligand (4-1BBL) in sustaining TLR-induced TNF production (PMID:17496895)
• Reverse signalling by CD137 ligand is mediated by protein tyrosine kinases, p38 mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1,2, MAP/ERK kinase (MEK), Phosphoinositide-3-kinase (PI3-K) and protein kinase A (PKA). (PMID:17855813)
• selective immunosuppression through MSCs may perhaps occur partly through an increase in CD137L+ on T-lymphocytes (PMID:17972956)
• T cells that had become non-responsive to anti-CD3 could be reactivated to proliferate when costimulated with 4-1BBL, either alone or combined with CD80/CD86. (PMID:17977894)
• CD80 and 4-1BBL induce auto- and transcostimulation in tumor cells (PMID:18026115)
• deliver new insights into the multiple effects of reverse signaling of CD137L in human DC during the initiation of an adaptive immune response (PMID:18395851)
• PGE(2) induced the expression of the costimulatory molecules OX40L, CD70, and 4-1BBL on human dendritic cells. (PMID:19029446)
• in cells costimulated with CD80/86 that had downregulated CD28 expression and ceased to proliferate, reactivation of proliferation by 4-1BBL costimulation also restored their CD28 expression (PMID:19217084)
• (c)4-1BBL can be expressed on mononuclear blood cells in acute myeloid leukemia, myelodysplasia or non-Hodgkin lymphoma and can be coexpressed on lymphoid or myeloid malignant cells and on dendritic cells differentiated from AML-blasts. (PMID:19225975)
• reverse signaling of 4-1BBL promotes the differentiation of potent T(h)1-inducing dendritic cells from human monocytes. (PMID:19684160)
• 4-1BBL and 4-1BB may have immunomodulatory functions, as shown by the anti-leukemia activity of MS-275 histone deacetylase inhibitor (PMID:19759901)
• Cocultures of Natural killer (NK) cells with CD137L transfectants confirmed that human CD137 inhibits NK-cell reactivity, while activating signals were transduced by its counterpart on NK cells in mice. (PMID:20008791)
• the structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily (PMID:20032458)
• TNFSF9 mRNA levels in peripheral blood mononuclear cells may be associated with primary biliary cirrhosis progression. (PMID:20303781)
• The expression of CD137L might play an important role in the development of laryngeal carcinomas. (PMID:20422976)
• These data point to a hitherto unrecognized role of CD137 and CD137 ligand in multiple myeloma cell biology. (PMID:20520765)
• K562-MICA-4-1BBL-IL-15 cells would be developed for expansion of NK cells ex vivo and may have important implications for clinical immunotherapy. (PMID:20670353)
• 4-1BBL and TRAF1 in the CD8 T cell response to influenza virus and HIV (PMID:21153322)
• Data indicate that ex4-1BBL augments 4-1BB expression not only on the primed T cell, but also on DC. (PMID:21745658)
• Stimulation of non-adherent PBMC with OVCAR-3 cells expressing 4-1BB ligand (4-1BBL) or IL-12 resulted in preferential expansion of the NK cell population. (PMID:22021067)
• signaling through CD137L in non-hematopoietic cells such as epithelial cells and endothelial cells has been shown to play an essential role in sterile inflammation by regulating immune cell recruitment. [Review] (PMID:22526397)
• this is the first study to indicate that this member of the TNF superfamily, CD137, is modulated by SAHA treatment in breast (PMID:22797667)
• CD137L is a novel diagnostic marker of subtypes of non-Hodgkin B-cell lymphomas. (PMID:23095505)
• Data show that TNFR1 associates with CD137L and is required for CD137L reverse signaling. (PMID:23620528)
• TIRAP and IRAK2 are critical for the sustained inflammatory response that is mediated by late-phase signaling by the TLR-4-1BBL complex. (PMID:24084649)
• Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy. (PMID:24198185)
• monocytes interact with iNKT cells to increase expression of 4-1BBL and 4-1BB, and in conjunction with this pathway, maintain their numbers at baseline. (PMID:24639347)
• Elevated plasma levels and monocyte-associated expression of CD137 ligand in patients with acute atherothrombotic stroke (PMID:24899613)
• CD137L is overexpressed in non-small cell lung cancer specimens and positive expression of CD137L was associated with better overall survival. (PMID:25631633)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnfsf9	ENSMUSG00000035678
rattus_norvegicus	Tnfsf9	ENSRNOG00000045595

Protein

Protein identifiers

Tumor necrosis factor ligand superfamily member 9 — P41273 (reviewed: P41273)

Alternative names: 4-1BB ligand

All UniProt accessions (2): P41273, A0A0U5J8I0

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to TNFRSF9. Induces the proliferation of activated peripheral blood T-cells. May have a role in activation-induced cell death (AICD). May play a role in cognate interactions between T-cells and B-cells/macrophages.

Subunit / interactions. Homotrimer.

Subcellular location. Membrane.

Tissue specificity. Expressed in brain, placenta, lung, skeletal muscle and kidney.

Similarity. Belongs to the tumor necrosis factor family.

RefSeq proteins (1): NP_003802* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006052	TNF_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR021184	TNF_CS	Conserved_site
IPR042373	TNFSF9	Family

Pfam: PF00229

UniProt features (26 total): strand 17, topological domain 2, turn 2, chain 1, transmembrane region 1, helix 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6MGP	X-RAY DIFFRACTION	2.13
2X29	X-RAY DIFFRACTION	2.3
6BWV	X-RAY DIFFRACTION	2.4
6CPR	X-RAY DIFFRACTION	2.7
6D3N	X-RAY DIFFRACTION	2.7
6FIB	X-RAY DIFFRACTION	2.7
6MGE	X-RAY DIFFRACTION	2.95
6CU0	X-RAY DIFFRACTION	3.2
6A3V	X-RAY DIFFRACTION	3.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41273-F1	77.20	0.49

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5669034	TNFs bind their physiological receptors

MSigDB gene sets: 303 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_92, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, ENK_UV_RESPONSE_KERATINOCYTE_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_CELL_CELL_SIGNALING, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION

GO Biological Process (9): immune response (GO:0006955), cell-cell signaling (GO:0007267), positive regulation of activated T cell proliferation (GO:0042104), regulation of T cell proliferation (GO:0042129), regulation of apoptotic process (GO:0042981), positive regulation of cytotoxic T cell differentiation (GO:0045585), cell communication (GO:0007154), signal transduction (GO:0007165), signaling (GO:0023052)

GO Molecular Function (5): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), tumor necrosis factor receptor superfamily binding (GO:0032813), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
cellular process	2
immune system process	1
response to stimulus	1
positive regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
T cell proliferation	1
regulation of lymphocyte proliferation	1
regulation of T cell activation	1
apoptotic process	1
regulation of programmed cell death	1
cytotoxic T cell differentiation	1
positive regulation of T cell differentiation	1
regulation of cytotoxic T cell differentiation	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of biological process	1
protein binding	1
receptor ligand activity	1
tumor necrosis factor receptor superfamily binding	1
cytokine receptor binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

996 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFSF9	TNFRSF9	Q07011	999
TNFSF9	TNFRSF4	P43489	997
TNFSF9	CD28	P10747	992
TNFSF9	CD27	P26842	982
TNFSF9	TNFSF4	P23510	907
TNFSF9	CD80	P33681	878
TNFSF9	ICOS	Q9Y6W8	877
TNFSF9	ICOSLG	O75144	873
TNFSF9	CD70	P32970	872
TNFSF9	A0A087X1L8	A0A087X1L8	870
TNFSF9	CD40LG	P29965	860
TNFSF9	TNFSF18	Q9UNG2	842
TNFSF9	TNFRSF8	P28908	815
TNFSF9	CD276	Q5ZPR3	796
TNFSF9	CD86	P42081	781

IntAct

133 interactions, top by confidence:

A	B	Type	Score
TNFRSF9	TNFSF9	psi-mi:“MI:0914”(association)	0.820
TNFSF9	TNFRSF9	psi-mi:“MI:0915”(physical association)	0.820
TNFSF9	TNFRSF9	psi-mi:“MI:0407”(direct interaction)	0.820
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
SLC39A5	TMEM223	psi-mi:“MI:0914”(association)	0.530
KLRG2	GXYLT2	psi-mi:“MI:0914”(association)	0.530
TMEM30B	KLRG2	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
FCGRT	GOLIM4	psi-mi:“MI:0914”(association)	0.530
CD1B	TOR1B	psi-mi:“MI:0914”(association)	0.530
OCLN	DNAJC13	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
MMP10	TIMP1	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
TNF	B4GALT5	psi-mi:“MI:0914”(association)	0.530

BioGRID (122): TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS)

ESM2 similar proteins: D3YZZ2, O00292, O43508, O54907, O55237, O75610, O75888, P10154, P26445, P32970, P41155, P41273, P70225, Q06600, Q13477, Q14626, Q3ZDR4, Q5E9Z9, Q5RF19, Q5T7M4, Q5WR07, Q63148, Q64280, Q64385, Q6BAA4, Q6UWL6, Q6ZMM2, Q862Z7, Q86UR1, Q8BHA1, Q8N1F8, Q8NAC3, Q8NFR9, Q8R2Z0, Q99M75, Q99MF4, Q99PI8, Q9BZR6, Q9C0J1, Q9D777

Diamond homologs: P41273, P41274

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 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
TNFs bind their physiological receptors	5	19.7×	8e-04
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	15	13.1×	1e-10

GO biological processes:

GO term	Partners	Fold	FDR
natural killer cell mediated cytotoxicity	5	16.5×	3e-03
negative regulation of T cell proliferation	5	12.6×	6e-03
adaptive immune response	13	8.4×	3e-06
immune response	21	7.5×	5e-10
cell surface receptor signaling pathway	11	5.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

349 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6534598:A:AG	acceptor_gain	1.0000
19:6534599:G:GA	acceptor_gain	1.0000
19:6534599:GTT:G	acceptor_gain	1.0000
19:6534599:GTTCT:G	acceptor_gain	1.0000
19:6531301:C:T	donor_gain	0.9900
19:6531301:CAG:C	donor_loss	0.9900
19:6531302:AGG:A	donor_loss	0.9900
19:6531303:GGT:G	donor_loss	0.9900
19:6531304:G:GA	donor_loss	0.9900
19:6532812:AAATG:A	donor_gain	0.9900
19:6532813:AATG:A	donor_gain	0.9900
19:6532814:ATG:A	donor_gain	0.9900
19:6532815:TG:T	donor_gain	0.9900
19:6532816:GG:G	donor_gain	0.9900
19:6532816:GGT:G	donor_loss	0.9900
19:6532817:G:GG	donor_gain	0.9900
19:6532817:GTA:G	donor_loss	0.9900
19:6532818:T:A	donor_loss	0.9900
19:6534594:CCACA:C	acceptor_loss	0.9900
19:6534595:CACA:C	acceptor_loss	0.9900
19:6534596:ACAG:A	acceptor_loss	0.9900
19:6534597:CA:C	acceptor_loss	0.9900
19:6534598:A:AC	acceptor_loss	0.9900
19:6534599:GT:G	acceptor_gain	0.9900
19:6534599:GTTC:G	acceptor_gain	0.9900
19:6531299:GGCAG:G	donor_gain	0.9700
19:6531300:GCAG:G	donor_gain	0.9700
19:6531300:GCAGG:G	donor_gain	0.9700
19:6532784:AG:A	acceptor_gain	0.9700
19:6532785:GG:G	acceptor_gain	0.9700

AlphaMissense

1566 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6534979:G:C	W226C	0.994
19:6534979:G:T	W226C	0.994
19:6534626:T:A	W109R	0.993
19:6534626:T:C	W109R	0.993
19:6534628:G:C	W109C	0.991
19:6534628:G:T	W109C	0.991
19:6534977:T:A	W226R	0.991
19:6534977:T:C	W226R	0.991
19:6532792:T:C	F92L	0.988
19:6532794:T:A	F92L	0.988
19:6532794:T:G	F92L	0.988
19:6534731:T:C	F144L	0.987
19:6534733:C:A	F144L	0.987
19:6534733:C:G	F144L	0.987
19:6534896:T:C	F199L	0.986
19:6534898:C:A	F199L	0.986
19:6534898:C:G	F199L	0.986
19:6535013:T:C	F238L	0.986
19:6535015:C:A	F238L	0.986
19:6535015:C:G	F238L	0.986
19:6534729:T:A	V143D	0.984
19:6534699:T:C	L133P	0.978
19:6535011:T:A	L237H	0.977
19:6534747:T:C	L149P	0.974
19:6535014:T:C	F238S	0.974
19:6534722:T:G	Y141D	0.973
19:6534627:G:C	W109S	0.969
19:6534716:G:A	G139R	0.968
19:6534716:G:C	G139R	0.968
19:6534717:G:T	G139V	0.968

dbSNP variants (sampled 300 via entrez): RS1000491087 (19:6532533 GTGTT>G), RS1000586506 (19:6536122 A>C), RS1000799869 (19:6531655 G>A), RS1001166752 (19:6531917 G>A,T), RS1001753441 (19:6530891 C>T), RS1001783074 (19:6534132 C>A,G,T), RS1002225440 (19:6530424 A>C), RS1003266757 (19:6534663 C>A,G,T), RS1004273493 (19:6532257 C>T), RS1005092409 (19:6530938 G>A,C,T), RS1005116719 (19:6536051 C>A), RS1005640235 (19:6533082 G>T), RS1006289560 (19:6529614 A>T), RS1006443677 (19:6536046 C>G), RS1006680366 (19:6533616 T>C)

Disease associations

OMIM: gene MIM:606182 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary predisposition to infections	Limited	Autosomal recessive

Mondo (1): (MONDO:0015979)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_622	Metabolite levels	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009793	isoleucine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	8
Benzo(a)pyrene	increases expression, increases methylation	6
Cisplatin	increases reaction, decreases expression, increases expression	5
Aflatoxin B1	affects expression, decreases methylation, increases expression	5
Cadmium Chloride	increases abundance, increases expression	5
sodium arsenite	increases expression	3
entinostat	increases reaction, increases expression, affects cotreatment	3
Cyclosporine	increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
trichostatin A	affects cotreatment, increases expression, increases reaction, decreases reaction	2
mercuric bromide	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression, increases reaction	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Anisomycin	increases expression, decreases expression	2
Cadmium	increases abundance, increases expression	2
Formaldehyde	increases expression	2
Oxygen	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
TL8-506	affects cotreatment, increases expression	1
chloroacetaldehyde	increases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
bis(tri-n-butyltin)oxide	increases expression	1
deoxynivalenol	decreases expression	1
lead acetate	increases expression	1
beta-lapachone	increases expression	1

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7IM	K562-mb15-41BBL	Cancer cell line	Female
CVCL_D1R0	Abcam K-562 TNFSF9 KO	Cancer cell line	Female
CVCL_D2ML	Abcam Raji TNFSF9 KO	Cancer cell line	Male
CVCL_E1J4	HyCyte ACHN KO-hTNFSF9	Cancer cell line	Male
CVCL_TT12	HAP1 TNFSF9 (-) 1	Cancer cell line	Male
CVCL_WQ69	Abcam Jurkat TNFSF9 KO	Cancer cell line	Male
CVCL_XU59	HAP1 TNFSF9 (-) 2	Cancer cell line	Male
CVCL_XU60	HAP1 TNFSF9 (-) 3	Cancer cell line	Male
CVCL_XY87	293T human CD137L	Transformed cell line	Female

Clinical trials (associated diseases)

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