TNFRSF14

Summary

TNFRSF14 (TNF receptor superfamily member 14, HGNC:11912) is a protein-coding gene on chromosome 1p36.32, encoding Tumor necrosis factor receptor superfamily member 14 (Q92956). Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signaling network.

This gene encodes a member of the TNF (tumor necrosis factor) receptor superfamily. The encoded protein functions in signal transduction pathways that activate inflammatory and inhibitory T-cell immune response. It binds herpes simplex virus (HSV) viral envelope glycoprotein D (gD), mediating its entry into cells. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8764 — RefSeq curated summary.

At a glance

• GWAS associations: 22
• Clinical variants (ClinVar): 86 total — 1 pathogenic
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• MANE Select transcript: NM_003820

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11912
Approved symbol	TNFRSF14
Name	TNF receptor superfamily member 14
Location	1p36.32
Locus type	gene with protein product
Status	Approved
Aliases	HVEM, ATAR, TR2, LIGHTR, HVEA, CD270
Ensembl gene	ENSG00000157873
Ensembl biotype	protein_coding
OMIM	602746
Entrez	8764

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 22 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000355716, ENST00000409119, ENST00000426449, ENST00000434817, ENST00000435221, ENST00000442392, ENST00000451778, ENST00000463471, ENST00000463835, ENST00000466750, ENST00000471768, ENST00000475523, ENST00000480305, ENST00000482074, ENST00000482602, ENST00000496064, ENST00000860781, ENST00000860782, ENST00000860783, ENST00000860784, ENST00000860785, ENST00000860786, ENST00000860787, ENST00000860788, ENST00000860789, ENST00000860790, ENST00000860791, ENST00000972443, ENST00000972444, ENST00000972445, ENST00000972446

RefSeq mRNA: 2 — MANE Select: NM_003820 NM_001297605, NM_003820

CCDS: CCDS44046

Canonical transcript exons

ENST00000355716 — 8 exons

Exon	Start	End
ENSE00001409963	2556371	2556733
ENSE00003526946	2559823	2559978
ENSE00003529037	2557726	2557834
ENSE00003537553	2558343	2558468
ENSE00003636931	2562865	2562896
ENSE00003641009	2563148	2563829
ENSE00003788417	2560624	2560714
ENSE00003791100	2561673	2561815

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.9136 / max 748.0319, expressed in 1477 samples.

FANTOM5 promoters (24 alternative TSS)

Promoter ID	TPM avg	Samples expressed
251	13.9928	994
248	10.5739	1413
239	3.2853	517
238	1.8909	571
242	1.5893	275
249	1.0539	524
246	0.9041	289
244	0.4756	225
250	0.3779	222
245	0.3606	217

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.89	gold quality
spleen	UBERON:0002106	98.75	gold quality
right uterine tube	UBERON:0001302	98.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.50	gold quality
duodenum	UBERON:0002114	98.33	gold quality
transverse colon	UBERON:0001157	98.25	gold quality
small intestine	UBERON:0002108	98.24	gold quality
mucosa of transverse colon	UBERON:0004991	98.06	gold quality
metanephros cortex	UBERON:0010533	98.02	gold quality
right adrenal gland cortex	UBERON:0035827	97.74	gold quality
endocervix	UBERON:0000458	97.73	gold quality
blood	UBERON:0000178	97.69	gold quality
mucosa of stomach	UBERON:0001199	97.60	gold quality
fundus of stomach	UBERON:0001160	97.54	gold quality
upper lobe of left lung	UBERON:0008952	97.51	gold quality
body of stomach	UBERON:0001161	97.50	gold quality
cortex of kidney	UBERON:0001225	97.47	gold quality
right lung	UBERON:0002167	97.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.42	gold quality
prostate gland	UBERON:0002367	97.40	gold quality
colon	UBERON:0001155	97.39	gold quality
left adrenal gland cortex	UBERON:0035825	97.32	gold quality
vermiform appendix	UBERON:0001154	97.21	gold quality
lymph node	UBERON:0000029	97.14	gold quality
minor salivary gland	UBERON:0001830	97.12	gold quality
left adrenal gland	UBERON:0001234	97.11	gold quality
gall bladder	UBERON:0002110	97.11	gold quality
right adrenal gland	UBERON:0001233	97.09	gold quality
intestine	UBERON:0000160	97.08	gold quality
left uterine tube	UBERON:0001303	97.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFIA

miRNA regulators (miRDB)

46 targeting TNFRSF14, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-637	97.91	64.05	1517

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest involvement of TNF superfamily receptor members and ligands in human atherosclerosis. TNFRSF14 (HVEM, TR2, LIGHTR)analysis, found this receptor in regions rich in CD68-positive macrophage-derived foam cells and HLA-DR-positive cells. (PMID:11742858)
• Crystallization and preliminary diffraction studies of the ectodomain of the envelope glycoprotein D from herpes simplex virus 1 alone and in complex with the ectodomain of the human receptor HveA (PMID:11976496)
• Data show that mRNA encoding LIGHT and its receptors [HVEM, LTbetaR, and TR6 (DcR3)] are present in placentas and cytotrophoblast cells at term. (PMID:12466117)
• association of HVEM and nectin-1 with lipid rafts during herpes simplex virus entry (PMID:12915568)
• sHVEM levels were elevated in sera of patients with allergic asthma, atopic dermatitis and rheumatoid arthritis (PMID:14749527)
• both nectin 1 and HVEM receptors play a role during HSV infection in vivo and both are highly efficient even at low levels of expression (PMID:15110526)
• HVEM binds to B T lymphocyte attenuator (BTLA), an Ig family member, which inhibits T cell proliferation. (PMID:15568026)
• Binding of HVEM to BTLA attenuates T cell activation, identifying HVEM/BTLA as a coinhibitory receptor pair. (PMID:15647361)
• in cells a complex forms through physical associations of HVEM, HSV-1 gD, and at least gH (PMID:15767456)
• both LTbetaR and HVEM can discriminatively mediate the expression of different genes in cultured human umbilical vein endothelial cells, including LIGHT, a proinflammatory cytokine (PMID:15917993)
• distinct herpesviruses target the HVEM-BTLA cosignaling pathway, suggesting the importance of this pathway in regulating T cell activation during host defenses. (PMID:16131544)
• 2.8-A crystal structure of the BTLA-HVEM complex shows that BTLA binds the N-terminal cysteine-rich domain of HVEM and employs a unique binding surface (PMID:16169851)
• Real-time RT-PCR confirmed up-regulation of IL-8, osteopontin, and TNFRSF14 and down-regulation of SAMeS and CD209 in AH. (PMID:16797773)
• HVEM, a membrane-bound receptor that protects against apoptosis, was expressed only on syncytiotrophoblast (PMID:17010447)
• HSV-1-gD-HveA interaction initiates a signal transduction pathway leading to NF-kappaB activation (PMID:17405920)
• Ca(2+)is a downstream mediator of the LIGHT/HVEM interaction in monocytes (PMID:17947707)
• CD160 serves as a negative regulator of CD4+ T cell activation through its interaction with HVEM. (PMID:18193050)
• Expression of entry receptors nectin-1 and HVEM prevent entry of HSV-1 into human conjunctival epithelium. (PMID:18502984)
• These results establish that HVEM is involved in NF-kappaB activation by herpes simplex virus 1 glycoprotein D. (PMID:18671825)
• LIGHT-mediated upregulation of PAR-2 in endothelial cells is mediated through the HVEM receptor, involving Jun N-terminal kinase signaling pathways. (PMID:19023130)
• HVEM-B and T lymphocyte attenuator bidirectional signaling may serve as a critical cell-survival system for lymphoid and epithelial cells (PMID:19332782)
• tumor necrosis factor receptor superfamily, member 14 (TNFRSF14) and signal regulatory protein, gamma (SIRPG) appear to contribute to gender difference in incidence of systemic lupus erythematosus. (PMID:19473566)
• Results provide evidence of an existing relationship between HVEM and obesity, which suggest that this TNF superfamily receptor could be involved in the pathogenesis of obesity and inflammation-related activity. (PMID:19680232)
• unknown killing effect of LIGHT through HVEM on a lymphoid malignancy is described. (PMID:19701890)
• results suggest that down-regulation of the BTLA-HVEM pathway may be involved in germinal center B-cell activation. (PMID:19762537)
• the HVEM-BTLA cis-complex competitively inhibits HVEM activation by ligands expressed in the surrounding microenvironment, thus helping maintain T cells in the naive state. (PMID:19915044)
• We have identified and replicated a novel gene-gene interaction between 2 polymorphisms of TNFRSF members in Spanish patients with RA, based on the hypothesis of shared pathogenic pathways in complex diseases. (PMID:20187130)
• Findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes. (PMID:20884631)
• Polymorphisms were associated with MS predisposition, with stronger effect in patients with HHV6 active replication-TNFRSF6B-rs4809330(*)A: P=0.028, OR=1.13; TNFRSF14-rs6684865(*)A: overall P=0.0008, OR=1.2. (PMID:20962851)
• data show that HVEM stimulatory signals promote experimental colitis driven by innate or adaptive immune cells (PMID:21533159)
• HVEM-BTLA cis complex provides intrinsic regulation in T cells serving as an interference mechanism silencing signals coming from the microenvironment. (PMID:21920726)
• TNFRSF14 appears to be a serious candidate gene that might contribute to follicular lymphoma development. (PMID:21941365)
• The results of a mutagenesis study of HVEM suggest that the CD160 binding region on HVEM was slightly different from, but overlapped with, the BTLA binding site. (PMID:21959263)
• Results indicate that mHVEM on leukocytes and sHVEM in sera may contribute to the development and/or progression of gastric cancer. (PMID:22113134)
• study described the expression and spatial distribution of HVEM and BTLA in rheumatoid arthritis synovial tissues, and results indicated that HVEM/BTLA may be involved in regulating the progress of joint inflammation (PMID:22179929)
• These results suggest that the C-terminal portion of the soluble HVEM ectodomain inhibits herpes simplex virus type 1 gD activation and that this effect is neutralized in the full-length form of HVEM in normal infection. (PMID:22239829)
• These findings support role for BTLA and/or HVEM as potential, novel diagnostic markers of innate immune response/status and as therapeutic targets of sepsis. (PMID:22459947)
• HVEM-B and T lymphocyte attenuator (BTLA) interactions impair minor histocompatibility antigen (MiHA)-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-stem cell transplantation. (PMID:22634623)
• BTLA and HVEM may have roles in graft rejection after kidney transplantation (PMID:23375291)
• Sequencing of TNFRSF14 located in the minimal region of loss in 1p36.32 showed nine mutations in pediatric follicular lymphoma. (PMID:23445872)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdr	ENSDARG00000004392
danio_rerio	tnfrsfa	ENSDARG00000004451
danio_rerio	cd40	ENSDARG00000054968
danio_rerio	nradd	ENSDARG00000057143
danio_rerio	tnfrsf1b	ENSDARG00000070165
danio_rerio	tnfrsf11a	ENSDARG00000087804
mus_musculus	Tnfrsf10b	ENSMUSG00000022074
mus_musculus	Tnfrsf14	ENSMUSG00000042333
rattus_norvegicus	Tnfrsf14	ENSRNOG00000013820
rattus_norvegicus	AABR07018323.1	ENSRNOG00000038483

Paralogs (21): FAS (ENSG00000026103), TNFRSF1B (ENSG00000028137), TNFRSF9 (ENSG00000049249), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), TNFRSF10A (ENSG00000104689), LTBR (ENSG00000111321), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), TNFRSF21 (ENSG00000146072), TNFRSF11B (ENSG00000164761), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF18 (ENSG00000186891), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 14 — Q92956 (reviewed: Q92956)

Alternative names: Herpes virus entry mediator A, Tumor necrosis factor receptor-like 2

All UniProt accessions (5): A0A0D9SF52, B9A034, Q92956, F6Q0M4, F6UPZ7

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signaling network. Signals via the TRAF2-TRAF3 E3 ligase pathway to promote immune cell survival and differentiation. Participates in bidirectional cell-cell contact signaling between antigen presenting cells and lymphocytes. In response to ligation of TNFSF14/LIGHT, delivers costimulatory signals to T cells, promoting cell proliferation and effector functions. Interacts with CD160 on NK cells, enhancing IFNG production and anti-tumor immune response. In the context of bacterial infection, acts as a signaling receptor on epithelial cells for CD160 from intraepithelial lymphocytes, triggering the production of antimicrobial proteins and pro-inflammatory cytokines. Upon binding to CD160 on activated CD4+ T cells, down-regulates CD28 costimulatory signaling, restricting memory and alloantigen-specific immune response. May interact in cis (on the same cell) or in trans (on other cells) with BTLA. In cis interactions, appears to play an immune regulatory role inhibiting in trans interactions in naive T cells to maintain a resting state. In trans interactions, can predominate during adaptive immune response to provide survival signals to effector T cells. (Microbial infection) Acts as a receptor for Herpes simplex virus 1/HHV-1. (Microbial infection) Acts as a receptor for Herpes simplex virus 2/HHV-2.

Subunit / interactions. Interacts with TRAF2, TRAF3 and TRAF5. Interacts (via CRD1/TNFR-Cys 1) with CD160; this interaction is direct. Interacts with LTA and TNFSF14. Interacts (via CRD1/TNFR-Cys 1) in cis and trans with BTLA; the cis interactions inhibits the trans interactions. (Microbial infection) Interacts with herpes simplex virus 1/HHV-1 envelope glycoprotein D. (Microbial infection) Interacts with herpes simplex virus 2/HHV-2 envelope glycoprotein D.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed, with the highest expression in lung, spleen and thymus. Expressed in a subpopulation of B cells and monocytes. Expressed in naive T cells.

Post-translational modifications. N-glycosylated.

Domain organisation. The cysteine rich domain I (CRD1/TNFR-Cys 1) is required for interaction with BY55 and BTLA.

Similarity. Belongs to the tumor necrosis factor receptor superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92956-1	1	yes
Q92956-2	2

RefSeq proteins (2): NP_001284534, NP_003811* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR022332	TNFR_14	Family
IPR034031	TNFRSF14/UL144_N	Domain

Pfam: PF00020

UniProt features (39 total): strand 11, disulfide bond 8, sequence variant 4, repeat 3, glycosylation site 2, topological domain 2, mutagenesis site 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, transmembrane region 1, helix 1, modified residue 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5T2Q	X-RAY DIFFRACTION	1.9
5T2R	X-RAY DIFFRACTION	2.1
4FHQ	X-RAY DIFFRACTION	2.25
4RSU	X-RAY DIFFRACTION	2.3
1JMA	X-RAY DIFFRACTION	2.65
2AW2	X-RAY DIFFRACTION	2.8
6NG3	X-RAY DIFFRACTION	2.88
7MSG	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92956-F1	79.54	0.50

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 (1): 240

Disulfide bonds (8): 42–53, 54–67, 57–75, 78–93, 96–111, 99–119, 121–138, 127–135

Glycosylation sites (2): 173, 110

Mutagenesis-validated functional residues (2):

Position	Phenotype
61	abolishes cis interactions with btla.
61	does not affect cis interactions with btla.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5669034	TNFs bind their physiological receptors
R-HSA-9927353	Co-inhibition by BTLA

MSigDB gene sets: 288 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (17): adaptive immune response (GO:0002250), positive regulation of cytokine production involved in immune response (GO:0002720), immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), T cell costimulation (GO:0031295), negative regulation of T cell proliferation (GO:0042130), innate immune response (GO:0045087), negative regulation of alpha-beta T cell proliferation (GO:0046642), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), negative regulation of adaptive immune memory response (GO:1905675), positive regulation of T cell migration (GO:2000406), immune system process (GO:0002376), apoptotic process (GO:0006915), signal transduction (GO:0007165), tumor necrosis factor-mediated signaling pathway (GO:0033209), symbiont entry into host cell (GO:0046718)

GO Molecular Function (7): virus receptor activity (GO:0001618), tumor necrosis factor receptor activity (GO:0005031), cytokine binding (GO:0019955), ubiquitin protein ligase binding (GO:0031625), receptor ligand activity (GO:0048018), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1
Regulation of T cell activation by CD28 family	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	2
signal transduction	2
defense response to bacterium	2
positive regulation of cytokine production	1
cytokine production involved in immune response	1
positive regulation of production of molecular mediator of immune response	1
regulation of cytokine production involved in immune response	1
immune system process	1
response to stimulus	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
defense response to symbiont	1
negative regulation of T cell proliferation	1
alpha-beta T cell proliferation	1
negative regulation of alpha-beta T cell activation	1
regulation of alpha-beta T cell proliferation	1
negative regulation of adaptive immune response	1
adaptive immune memory response	1
regulation of adaptive immune memory response	1
T cell migration	1
positive regulation of lymphocyte migration	1
regulation of T cell migration	1
biological_process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
viral life cycle	1
symbiont entry into host	1
symbiont entry into host cell	1

Protein interactions and networks

STRING

1742 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF14	BTLA	Q7Z6A9	999
TNFRSF14	TNFSF14	O43557	999
TNFRSF14	CD160	O95971	998
TNFRSF14	ACKR1	Q16570	998
TNFRSF14	LTA	P01374	992
TNFRSF14	ERVW-1	Q9UQF0	965
TNFRSF14	TNF	P01375	904
TNFRSF14	NECTIN1	Q15223	887
TNFRSF14	TNFRSF8	P28908	850
TNFRSF14	NECTIN2	Q92692	822
TNFRSF14	LGALS9	O00182	822
TNFRSF14	TRAF5	O00463	820
TNFRSF14	TNFRSF4	P43489	820
TNFRSF14	PILRA	Q9UKJ1	818
TNFRSF14	LTB	P78370	798

IntAct

122 interactions, top by confidence:

A	B	Type	Score
TNFSF14	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.810
TNFRSF14	TNFSF14	psi-mi:“MI:0915”(physical association)	0.810
TNFSF14	TNFRSF14	psi-mi:“MI:0407”(direct interaction)	0.810
TNFRSF14	TRAF2	psi-mi:“MI:0915”(physical association)	0.690
TRAF2	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.690
TNFRSF14	TRAF5	psi-mi:“MI:0915”(physical association)	0.650
TNFRSF14	TRAF2	psi-mi:“MI:0915”(physical association)	0.650
TRAF2	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.650
TRAF5	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.650
TNFRSF14	BTLA	psi-mi:“MI:0915”(physical association)	0.610
TNFRSF14	CD160	psi-mi:“MI:0915”(physical association)	0.610
BTLA	TNFRSF14	psi-mi:“MI:0407”(direct interaction)	0.610
CD160	TNFRSF14	psi-mi:“MI:0407”(direct interaction)	0.610
TNFRSF14	FOXD4L6	psi-mi:“MI:0915”(physical association)	0.560
TNFRSF14	AKT1	psi-mi:“MI:2364”(proximity)	0.470
AKT1	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.470
gD	TNFRSF14	psi-mi:“MI:0407”(direct interaction)	0.440
GRB2	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.400
TRAF1	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.400
TRAF3	TNFRSF14	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (41): UGGT1 (Affinity Capture-MS), GCN1L1 (Affinity Capture-MS), P4HB (Affinity Capture-MS), SEC11A (Affinity Capture-MS), PDIA6 (Affinity Capture-MS), CHD3 (Two-hybrid), VIM (Two-hybrid), TNFRSF14 (Reconstituted Complex), TRAF5 (Two-hybrid), TRAF2 (Two-hybrid), TRAF2 (Affinity Capture-Western), TRAF5 (Affinity Capture-Western), TNFRSF14 (Affinity Capture-Western), TNFRSF14 (Affinity Capture-RNA), TRAF5 (Reconstituted Complex)

ESM2 similar proteins: D4A6L0, E1BBQ2, O19131, P07174, P08138, P18519, P19438, P20959, P21744, P22692, P22934, P24591, P24854, P25118, P25942, P41272, P43489, P47741, P47879, P50555, P98174, Q05716, Q0VCT3, Q28203, Q3LRP1, Q3ZTK5, Q496Y0, Q4R4I0, Q5EAN7, Q5T848, Q5VV43, Q6UWJ8, Q7YRL5, Q8BX43, Q8C088, Q8C419, Q8HXH0, Q8K5A9, Q8SQ34, Q91VL8

Diamond homologs: O14763, O19131, O73559, P0DSV7, P0DSV8, P0DTN0, P19438, P22934, P25118, P25943, P50555, P68636, P68637, Q80WY6, Q92956, Q9ER62, Q9ER63, O14798, O77736, P25445, P25446, P47741, P51867, Q3ZTK5, Q63199, Q80WM9, Q8SQ34, Q9BDN0, Q9BDN4, Q9BDP2, Q9TSN4, A5D7R1, D3ZF92, O00300, O08712, O08727, O35305, O75509, O95407, P20333

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TNFRSF14	“up-regulates activity”	TRAF5	binding
TNFSF14	up-regulates	TNFRSF14	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 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
TNFR2 non-canonical NF-kB pathway	6	16.2×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
tumor necrosis factor-mediated signaling pathway	5	21.5×	1e-03
epidermal growth factor receptor signaling pathway	5	16.1×	4e-03
protein folding	9	12.1×	5e-05
regulation of apoptotic process	8	8.7×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — DLBCLNOS, MLYM, NHL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	34
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
154584	GRCh38/hg38 1p36.33-36.23(chr1:898721-7811306)x1	Pathogenic

SpliceAI

1496 predictions. Top by Δscore:

Variant	Effect	Δscore
1:2559974:GGGAG:G	donor_gain	1.0000
1:2559975:GGAGG:G	donor_gain	1.0000
1:2559976:G:T	donor_gain	1.0000
1:2560620:TCA:T	acceptor_loss	1.0000
1:2560621:CAG:C	acceptor_loss	1.0000
1:2560622:A:AG	acceptor_gain	1.0000
1:2560623:G:GC	acceptor_loss	1.0000
1:2560623:G:GG	acceptor_gain	1.0000
1:2560623:GGC:G	acceptor_gain	1.0000
1:2560710:ACCAA:A	donor_gain	1.0000
1:2560711:CCAA:C	donor_gain	1.0000
1:2560712:CAA:C	donor_gain	1.0000
1:2560712:CAAG:C	donor_loss	1.0000
1:2560713:AA:A	donor_gain	1.0000
1:2560715:G:GG	donor_gain	1.0000
1:2560715:GTA:G	donor_loss	1.0000
1:2557723:TA:T	acceptor_loss	0.9900
1:2557724:A:AG	acceptor_gain	0.9900
1:2557724:A:G	acceptor_loss	0.9900
1:2557725:G:A	acceptor_loss	0.9900
1:2557725:G:GG	acceptor_gain	0.9900
1:2557725:GGT:G	acceptor_gain	0.9900
1:2557835:G:GG	donor_gain	0.9900
1:2558338:GGCA:G	acceptor_loss	0.9900
1:2558340:CA:C	acceptor_loss	0.9900
1:2558341:AGGTT:A	acceptor_loss	0.9900
1:2559976:G:GT	donor_gain	0.9900
1:2559976:GAGG:G	donor_loss	0.9900
1:2559977:AGGT:A	donor_loss	0.9900
1:2559978:GGT:G	donor_loss	0.9900

AlphaMissense

1833 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:2557834:G:T	G60C	0.987
1:2558428:T:A	N88K	0.985
1:2558428:T:G	N88K	0.985
1:2557796:A:G	Y47C	0.984
1:2559894:T:C	F126L	0.975
1:2559896:C:A	F126L	0.975
1:2559896:C:G	F126L	0.975
1:2558343:G:T	G60V	0.974
1:2558427:A:T	N88I	0.974
1:2558441:T:A	C93S	0.973
1:2558442:G:C	C93S	0.973
1:2557825:T:A	C57S	0.971
1:2557826:G:C	C57S	0.971
1:2558387:T:A	C75S	0.968
1:2558388:G:C	C75S	0.968
1:2558396:T:A	C78S	0.967
1:2558397:G:C	C78S	0.967
1:2558343:G:A	G60D	0.964
1:2558441:T:C	C93R	0.963
1:2558397:G:A	C78Y	0.962
1:2558398:C:G	C78W	0.961
1:2558411:T:G	Y83D	0.960
1:2558349:G:C	R62P	0.959
1:2558396:T:C	C78R	0.959
1:2557834:G:C	G60R	0.957
1:2557796:A:C	Y47S	0.956
1:2558388:G:A	C75Y	0.954
1:2557825:T:C	C57R	0.953
1:2559897:T:A	C127S	0.950
1:2559898:G:C	C127S	0.950

dbSNP variants (sampled 300 via entrez): RS1000369065 (1:2558100 G>A), RS1000783418 (1:2560154 G>C), RS1000874025 (1:2555022 G>T), RS1001314482 (1:2557221 G>A), RS1001572154 (1:2563614 G>A), RS1001604955 (1:2563431 G>A), RS1001686386 (1:2558887 G>A,T), RS1001834895 (1:2554262 A>G,T), RS1002373400 (1:2555923 G>A), RS1002421061 (1:2560919 C>T), RS1002573488 (1:2562747 G>A), RS1002839946 (1:2553394 A>G), RS1002913482 (1:2553178 T>A,G), RS1002975619 (1:2553643 C>G,T), RS1003272745 (1:2554960 A>T)

Disease associations

OMIM: gene MIM:602746 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000232_1	Rheumatoid arthritis	1.000000e-07
GCST000612_12	Celiac disease	3.000000e-09
GCST000964_38	Ulcerative colitis	3.000000e-09
GCST001728_20	Ulcerative colitis	3.000000e-12
GCST002318_126	Rheumatoid arthritis	8.000000e-14
GCST002318_127	Rheumatoid arthritis	5.000000e-09
GCST002318_33	Rheumatoid arthritis	8.000000e-07
GCST002323_1	Rheumatoid arthritis	1.000000e-06
GCST004131_113	Inflammatory bowel disease	8.000000e-07
GCST004133_54	Ulcerative colitis	1.000000e-10
GCST004290_2	Multiple sclerosis	1.000000e-06
GCST005038_27	Allergic disease (asthma, hay fever or eczema)	3.000000e-08
GCST005537_123	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	2.000000e-11
GCST005951_35	Body mass index	4.000000e-08
GCST006670_4	Primary sclerosing cholangitis	7.000000e-12
GCST006959_144	Rheumatoid arthritis	4.000000e-14
GCST006959_62	Rheumatoid arthritis	2.000000e-10
GCST007932_86	Medication use (thyroid preparations)	9.000000e-10
GCST008483_1	Ulcerative colitis	2.000000e-06
GCST010571_1	Autoimmune thyroid disease	2.000000e-11
GCST90002381_508	Eosinophil count	1.000000e-11
GCST90002382_51	Eosinophil percentage of white cells	2.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0009933	Thyroid preparation use measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Immune checkpoint catalytic receptors

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	3
Tretinoin	increases expression	3
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	increases expression	2
Cisplatin	increases expression, increases reaction	2
Ozone	affects expression, increases abundance, affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
FR900359	decreases phosphorylation	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	increases expression	1
sodium arsenate	increases abundance, increases expression	1
methylparaben	decreases expression	1
o,p’-DDT	increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	decreases expression	1
exemestane	increases expression	1
tamibarotene	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
jinfukang	increases expression, increases reaction	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Aripiprazole	decreases expression, affects cotreatment	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1

Cellosaurus cell lines

5 cell lines: 3 spontaneously immortalized cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E5IU	CHO-K1/HVEM	Spontaneously immortalized cell line	Female
CVCL_E6S1	Genomeditech CHO-K1 H_TNFRSF14(HVEM)	Spontaneously immortalized cell line	Female
CVCL_E6S2	Genomeditech CHO-K1 H_TNFRSF14(HVEM) aAPC	Spontaneously immortalized cell line	Female
CVCL_E6W0	Genomeditech Jurkat H_TNFRSF14(HVEM) Reporter	Cancer cell line	Male
CVCL_WV42	LB5871-LYMP	Cancer cell line	Female

Clinical trials (associated diseases)

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