TNFRSF25

Summary

TNFRSF25 (TNF receptor superfamily member 25, HGNC:11910) is a protein-coding gene on chromosome 1p36.31, encoding Tumor necrosis factor receptor superfamily member 25 (Q93038). Receptor for TNFSF12/APO3L/TWEAK.

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed preferentially in the tissues enriched in lymphocytes, and it may play a role in regulating lymphocyte homeostasis. This receptor has been shown to stimulate NF-kappa B activity and regulate cell apoptosis. The signal transduction of this receptor is mediated by various death domain containing adaptor proteins. Knockout studies in mice suggested the role of this gene in the removal of self-reactive T cells in the thymus. Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules. The alternative splicing of this gene in B and T cells encounters a programmed change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation.

Source: NCBI Gene 8718 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 79 total
• MANE Select transcript: NM_003790

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11910
Approved symbol	TNFRSF25
Name	TNF receptor superfamily member 25
Location	1p36.31
Locus type	gene with protein product
Status	Approved
Aliases	DR3, TRAMP, WSL-1, LARD, WSL-LR, DDR3, TR3, APO-3
Ensembl gene	ENSG00000215788
Ensembl biotype	protein_coding
OMIM	603366
Entrez	8718

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 9 protein_coding, 6 nonsense_mediated_decay, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000348333, ENST00000351748, ENST00000351959, ENST00000356876, ENST00000377782, ENST00000414040, ENST00000453260, ENST00000453341, ENST00000461703, ENST00000469691, ENST00000473343, ENST00000475730, ENST00000480393, ENST00000481401, ENST00000485036, ENST00000502588, ENST00000502730, ENST00000510563, ENST00000513135, ENST00000515145, ENST00000647810, ENST00000871991, ENST00000925609

RefSeq mRNA: 6 — MANE Select: NM_003790 NM_001039664, NM_003790, NM_148965, NM_148966, NM_148967, NM_148970

CCDS: CCDS71, CCDS72, CCDS73, CCDS74, CCDS75

Canonical transcript exons

ENST00000356876 — 10 exons

Exon	Start	End
ENSE00001847819	6466069	6466173
ENSE00003476297	6464375	6464453
ENSE00003477098	6462629	6462666
ENSE00003572411	6465440	6465560
ENSE00003583734	6463072	6463127
ENSE00003628494	6465088	6465222
ENSE00003634537	6461994	6462174
ENSE00003649252	6464552	6464719
ENSE00003684931	6462863	6462970
ENSE00003840057	6460786	6461762

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 99.26.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2393 / max 172.4112, expressed in 201 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10036	3.1194	192
10035	0.1199	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.26	gold quality
cerebellar hemisphere	UBERON:0002245	99.25	gold quality
cerebellar cortex	UBERON:0002129	99.17	gold quality
cerebellum	UBERON:0002037	98.27	gold quality
lower esophagus mucosa	UBERON:0035834	97.67	gold quality
adenohypophysis	UBERON:0002196	97.23	gold quality
granulocyte	CL:0000094	96.10	gold quality
skin of abdomen	UBERON:0001416	96.06	gold quality
pituitary gland	UBERON:0000007	95.85	gold quality
skin of leg	UBERON:0001511	95.45	gold quality
right frontal lobe	UBERON:0002810	95.23	gold quality
right uterine tube	UBERON:0001302	94.81	gold quality
spleen	UBERON:0002106	94.73	gold quality
mucosa of transverse colon	UBERON:0004991	93.97	gold quality
sural nerve	UBERON:0015488	92.98	gold quality
apex of heart	UBERON:0002098	92.97	gold quality
tibial nerve	UBERON:0001323	92.85	gold quality
zone of skin	UBERON:0000014	92.13	gold quality
esophagus mucosa	UBERON:0002469	91.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.05	gold quality
lymph node	UBERON:0000029	89.93	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.77	gold quality
cingulate cortex	UBERON:0003027	89.44	gold quality
anterior cingulate cortex	UBERON:0009835	89.36	gold quality
paraflocculus	UBERON:0005351	89.09	gold quality
transverse colon	UBERON:0001157	88.85	gold quality
nucleus accumbens	UBERON:0001882	88.13	gold quality
cerebellar vermis	UBERON:0004720	87.82	gold quality
small intestine	UBERON:0002108	87.60	gold quality
ganglionic eminence	UBERON:0004023	87.37	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-84	yes	546.58
E-CURD-88	yes	22.43
E-CURD-46	yes	13.00
E-MTAB-6701	yes	11.74
E-MTAB-6678	yes	5.22
E-ANND-3	yes	4.95
E-CURD-112	no	3.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKBID, NR1I2

miRNA regulators (miRDB)

5 targeting TNFRSF25, 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-3618	99.69	68.57	1012
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-6815-5P	96.05	65.55	662
HSA-MIR-6865-5P	96.05	65.58	675
HSA-MIR-6850-3P	88.96	69.27	33

Literature-anchored findings (GeneRIF, showing 40)

• These data confirm that silencer of death domains (SODD) and death receptor 3 (DR3) are expressed in a regulated manner during renal transplant rejection, and identify DR3 as a potential inducible mediator of tubular inflammation and injury. (PMID:12875962)
• TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis (PMID:12882979)
• Death receptor 3 gene duplication is associated with rheumatoid arthritis (PMID:15241467)
• TL1A and DR3 is involved in atherosclerosis via the induction of pro-inflammatory cytokines/chemokines (PMID:15760679)
• VEGI gene expression is subject to regulation by inflammatory cytokines. VEGI is also able to regulate the expression of several important genes involved in angiogenesis. (PMID:16517446)
• Results suggest that death receptor-3 activation can mediate apoptosis in osteoblasts, although its activity is highly restricted by its soluble ligand-binding isoform and possibly also by alternate survival signals. (PMID:16986165)
• These results suggest that caspase-10, DR-3 and IGFBP-3 are involved in apoptosis in the preeclamptic placenta. (PMID:17085968)
• TNFR25/TL1A pair provides an early signal for cytokine production in the lung, and therefore may be a drug target in attempts to attenuate lung inflammation in asthmatics. (PMID:18411341)
• HLA-B8 and DR3 haplotype is associated with graft failure after renal transplantation in patients with underlying immunoglobulin A nephropathy (PMID:19674013)
• critically involved in the pathogenesis of rheumatoid arthritis (PMID:20125169)
• role of TNFRSF25:TNFSF15 in disease and health (PMID:21153333)
• in active psoriasis, we observed abundant immunostaining for TL1A and significant upregulation of its receptors DR3 and DcR3 (PMID:21672030)
• Investigated further the mechanisms by which the E-selectin-activated pathways downstream of DR3 confer a survival advantage to colon cancer cells. (PMID:21722370)
• It was shown that IL-32 enhanced the cytotoxic effect of natural killer cells on protate cancer cells through activation of DR3 and caspase-3. (PMID:22043900)
• Protein expression of tumour necrosis factor (TNF)-like ligand 1A (TL1A) and death-domain receptor (DR)3 is upregulated in the aged bladder tissues. (PMID:22641456)
• Both TNFRSF25 and TNFRSF4 independently and additively costimulate vaccine-induced CD8+ T cell proliferation following both primary and secondary antigen challenge. (PMID:22956587)
• Collectively, these data suggest a complex role for DR3 in breast cancer development and progression (PMID:23443464)
• TRAMP mice fed with 3’-diindolylmethane-supplemented diet show much lower incidence of tumorigenesis and metastasis than the untreated control group. (PMID:23658110)
• These results suggested that TL1A could promote Th17 differentiation in rheumatoid arthritis via the activation of RORc, and this effect may be mediated by the binding of TL1A with DR3. (PMID:24832108)
• DR-3 drives early cartilage destruction in the antigen-induced model of inflammatory arthritis through the release of CXCL1, maximizing neutrophil recruitment to the joint and leading to enhanced local production of cartilage-destroying enzymes. (PMID:25044706)
• Suggest tectochrysin leads to apoptotic cell death in NSCLC cells through activation of DR3 and Fas expression via inhibition of STAT3 phosphorylation. (PMID:25083589)
• Human memory IL-18Ralpha and DR3 CD4+ T cells may contribute to antigen-independent innate responses at barrier surfaces. (PMID:25269704)
• Silencing of the DR3 gene affect levels of apoptosis antigen3 ligand in cells. (PMID:25370568)
• DR3 is expressed in some interstitial vascular endothelial cells in human kidney in situ. These EC also respond to TL1A by activating NF-kappaB. Very low levels of DR3 are seen on the cell surface of HUVEC, which do not respond to TL1A. (PMID:25399326)
• Distinctions in occurrence of spectrums of DR3/LARD mRNA at healthy volunteers and colon cancer patients can define a different susceptibility of immunocompetent and tumor cells for apoptosis (PMID:25509355)
• The changes in frequency of occurrence of spliced variants of DR3/LARD mRNA were directed towards modulation of apoptosis and restraint of antiviral immune response. (PMID:25929035)
• DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC3s). (PMID:26046454)
• These data identify new roles for DR3 in regulating OB-dependent bone mineral apposition. (PMID:26065008)
• Higher DR3 levels were associated with early stage chronic lymphocytic leukemia. (PMID:26393680)
• DR3 is efficiently activated by soluble TL1A trimers. (PMID:26509650)
• Biologics beyond TNF-alpha inhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders. (PMID:26810853)
• Untreated children with IBD have higher percentage of DR3(+) PBMCs. (PMID:27001939)
• In addition to apoptosis, DR3 can robustly trigger necroptotic cell death and provide evidence for TL1A-induced, DR3-mediated necrosome assembly. DR3-mediated necroptosis critically depends on receptor-interacting protein 1 (RIP1) and RIP3, the core components of the necroptotic machinery, which activate the pseudo-kinase mixed lineage kinase domain-like, the prototypic downstream effector molecule of necroptosis. (PMID:27592300)
• These results raise the possibility for involvement of TL1A/DR3/DR3-mediated mechanisms in epithelial-mesenchymal interactions and the development of inflammation-induced intestinal fibrosis in Crohn’s disease. (PMID:27665176)
• Activation of DR3 is accompanied by inhibition of apoptosis of naive T-lymphocytes in children with acute infectious mononucleosis. (PMID:27682848)
• the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9. (PMID:28062298)
• Data suggest that human regulatory T-lymphocytes express DR3 and demonstrate DR3/TL1A-mediated activation of signaling via MAP kinases and NFkappaB. (DR3 = death receptor 3; TL1A/TNFSF15 = tumor necrosis factor [ligand] superfamily, member 15) (PMID:28337757)
• Hypermethylation of the proapoptotic genes BCL2 L11 and TNFRSF25 is observed in pleomorphic adenoma of the salivary glands. However, this phenomenon did not impact mRNA transcription. (PMID:28941993)
• Pathologic up-regulation of TNFSF15-TNFRSF25 axis sustains endothelial dysfunction in unprovoked venous thromboembolism. (PMID:31135876)
• In contrast to pre-menopausal females, post-menopausal serum levels of TL1A are not significantly elevated and that DR3 expression is not induced on CD14+ monocytes. Murine ovariectomy (OVX) model of estrogen-deficiency revealed that early post-OVX expression of DR3 on CD4+ T cells is significantly elevated suggesting that DR3 and TL1A could play a potentially indirect role in early post-menopausal bone loss. (PMID:31299941)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	hdr	ENSDARG00000004392
danio_rerio	tnfrsfa	ENSDARG00000004451
danio_rerio	cd40	ENSDARG00000054968
danio_rerio	tnfrsf1b	ENSDARG00000070165
danio_rerio	tnfrsf11a	ENSDARG00000087804
mus_musculus	Tnfrsf25	ENSMUSG00000024793
rattus_norvegicus	Tnfrsf25	ENSRNOG00000021814

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), TNFRSF14 (ENSG00000157873), TNFRSF11B (ENSG00000164761), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF18 (ENSG00000186891), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 25 — Q93038 (reviewed: Q93038)

Alternative names: Apo-3, Apoptosis-inducing receptor AIR, Apoptosis-mediating receptor DR3, Apoptosis-mediating receptor TRAMP, Death receptor 3, Lymphocyte-associated receptor of death, Protein WSL, Protein WSL-1

All UniProt accessions (4): Q93038, A0A0C4DGF3, A0A3B3ISD9, K7EJY9

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for TNFSF12/APO3L/TWEAK. Interacts directly with the adapter TRADD. Mediates activation of NF-kappa-B and induces apoptosis. May play a role in regulating lymphocyte homeostasis.

Subunit / interactions. Homodimer. Interacts strongly via the death domains with TNFRSF1 and TRADD to activate at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Interacts with BAG4.

Subcellular location. Cell membrane Cell membrane Cell membrane Cell membrane Secreted Secreted Secreted Secreted Secreted Secreted Secreted Secreted.

Tissue specificity. Abundantly expressed in thymocytes and lymphocytes. Detected in lymphocyte-rich tissues such as thymus, colon, intestine, and spleen. Also found in the prostate.

Post-translational modifications. (Microbial infection) Glycosylated at Arg-352 by enteropathogenic E.coli protein NleB1. Glycosylated.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (12)

UniProt ID	Names	Canonical?
Q93038-1	1, WSL-1, LARD-1A	yes
Q93038-2	2, LARD-1B
Q93038-3	3, WSL-S1, LARD-3
Q93038-4	4, WSL-S2, LARD-2
Q93038-5	5, LARD-4, LARD-11
Q93038-6	6, LARD-5
Q93038-7	7, LARD-6
Q93038-8	8, LARD-7
Q93038-9	9, LARD-8
Q93038-10	10, LARD-9
Q93038-11	11, Beta
Q93038-12	12, Beta soluble

RefSeq proteins (6): NP_001034753, NP_003781, NP_683866, NP_683867, NP_683868, NP_683871 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR022329	TNFR_25	Family
IPR034050	TNFRSF25_N	Domain

Pfam: PF00020, PF00531

UniProt features (59 total): splice variant 14, disulfide bond 12, helix 6, sequence variant 5, sequence conflict 4, repeat 4, glycosylation site 3, mutagenesis site 3, topological domain 2, turn 2, signal peptide 1, chain 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5YGP	X-RAY DIFFRACTION	2.09
5YEV	X-RAY DIFFRACTION	2.5
5YGS	X-RAY DIFFRACTION	2.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q93038-F1	72.98	0.43

Functional residue map

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

Disulfide bonds (12): 35–47, 48–61, 51–70, 73–89, 92–107, 95–115, 117–130, 138–155, 141–162, 165–176, 179–191, 187–195

Glycosylation sites (3): 67, 106, 352

Mutagenesis-validated functional residues (3):

Position	Phenotype
354	suppresses homodimerization, tnfr1 interaction, and apoptosis induction.
356	suppresses homodimerization, and tnfr1 interaction.
373	suppresses homodimerization, and tnfr1 interaction.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 234 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, MORF_RAGE, MORF_FLT1, CAR_TNFRSF25, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, PEREZ_TP63_TARGETS, MODULE_45, MODULE_64, MORF_ATRX, WHITE_NEUROBLASTOMA_WITH_1P36.3_DELETION, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP

GO Biological Process (6): apoptotic process (GO:0006915), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), regulation of apoptotic process (GO:0042981), apoptotic signaling pathway (GO:0097190), tumor necrosis factor-mediated signaling pathway (GO:0033209)

GO Molecular Function (3): tumor necrosis factor receptor activity (GO:0005031), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), cytosol (GO:0005829), 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
cellular anatomical structure	3
signal transduction	2
apoptotic process	2
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
regulation of programmed cell death	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
death receptor activity	1
tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor binding	1
molecular transducer activity	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

2 interactions, top by confidence:

A	B	Type	Score
DYRK1A	TNFRSF25	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): KDR (Affinity Capture-Western), PTPN6 (Affinity Capture-Western), TNFRSF25 (Affinity Capture-Western), KDR (Co-localization), PTPN6 (Co-localization), TRADD (Two-hybrid), BAG4 (Affinity Capture-Western), DAP3 (Reconstituted Complex), TNFRSF25 (Affinity Capture-RNA), TNFRSF25 (Affinity Capture-Western), TNFRSF25 (Affinity Capture-RNA), NOL3 (Phenotypic Suppression), TNFRSF25 (Two-hybrid), TRADD (Affinity Capture-Western), TNFRSF25 (Two-hybrid)

ESM2 similar proteins: A4FV93, A5A8Y8, B2LW77, D3ZUK3, O00468, O70534, O75074, O88204, O88839, O95407, P06579, P07204, P15306, P60882, P80370, Q09163, Q13444, Q14162, Q3SWY4, Q501P1, Q53RD9, Q5ND28, Q5VY43, Q5W7P8, Q61810, Q6AZ60, Q6GUQ1, Q6MG84, Q6UY11, Q71U07, Q75N90, Q7Z7M0, Q8K1E3, Q8K1S7, Q8K4G1, Q8NCW0, Q8ND94, Q8VIK5, Q8WUT4, Q93038

Diamond homologs: Q93038, Q9ER62, Q9ER63, O19131, P0DTN0, P18519, P22934, P25118, P83626, O73559, P0DSV7, P0DSV8, P50555, P68636, P68637

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TNFRSF25	up-regulates	TRADD	binding
TNFSF15	up-regulates	TNFRSF25	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	11
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1161 predictions. Top by Δscore:

Variant	Effect	Δscore
1:6461900:T:C	acceptor_gain	1.0000
1:6461900:T:TC	acceptor_gain	1.0000
1:6462171:TGGC:T	acceptor_gain	1.0000
1:6462172:GGC:G	acceptor_gain	1.0000
1:6462173:GC:G	acceptor_gain	1.0000
1:6462173:GCCTG:G	acceptor_loss	1.0000
1:6462174:CC:C	acceptor_gain	1.0000
1:6462175:C:A	acceptor_loss	1.0000
1:6462175:C:CC	acceptor_gain	1.0000
1:6462176:T:A	acceptor_loss	1.0000
1:6464346:C:A	donor_gain	1.0000
1:6464391:AG:A	donor_gain	1.0000
1:6464392:G:C	donor_gain	1.0000
1:6464716:GAGG:G	acceptor_gain	1.0000
1:6464720:C:CC	acceptor_gain	1.0000
1:6464729:G:C	acceptor_gain	1.0000
1:6465086:AC:A	donor_gain	1.0000
1:6465087:CC:C	donor_gain	1.0000
1:6465087:CCCTG:C	donor_gain	1.0000
1:6461897:CAGT:C	acceptor_gain	0.9900
1:6461898:A:T	acceptor_gain	0.9900
1:6462170:GTGGC:G	acceptor_gain	0.9900
1:6462664:C:CC	acceptor_gain	0.9900
1:6462665:T:G	acceptor_loss	0.9900
1:6462667:C:CC	acceptor_gain	0.9900
1:6463070:A:AC	donor_gain	0.9900
1:6463071:C:CC	donor_gain	0.9900
1:6463071:CT:C	donor_gain	0.9900
1:6464373:A:AC	donor_gain	0.9900
1:6464374:C:CC	donor_gain	0.9900

AlphaMissense

2691 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:6461647:C:A	W347C	0.999
1:6461647:C:G	W347C	0.999
1:6461649:A:G	W347R	0.999
1:6461649:A:T	W347R	0.999
1:6461663:A:T	V342D	0.999
1:6461544:A:G	W382R	0.998
1:6461544:A:T	W382R	0.998
1:6461639:A:G	F350S	0.998
1:6461542:C:A	W382C	0.997
1:6461542:C:G	W382C	0.997
1:6461634:G:T	R352S	0.997
1:6461552:A:T	L379H	0.996
1:6461555:A:C	M378R	0.996
1:6461633:C:G	R352P	0.996
1:6461644:C:A	K348N	0.996
1:6461644:C:G	K348N	0.996
1:6461555:A:G	M378T	0.995
1:6461639:A:C	F350C	0.995
1:6461648:C:G	W347S	0.995
1:6461552:A:G	L379P	0.994
1:6461554:C:A	M378I	0.994
1:6461554:C:G	M378I	0.994
1:6461554:C:T	M378I	0.994
1:6461546:C:G	R381P	0.992
1:6461561:T:C	Y376C	0.992
1:6465149:G:C	F78L	0.992
1:6465149:G:T	F78L	0.992
1:6465151:A:G	F78L	0.992
1:6461462:A:G	L409S	0.991
1:6461489:A:G	M400T	0.991

dbSNP variants (sampled 300 via entrez): RS1000130641 (1:6461260 T>G), RS1000383795 (1:6464253 G>A,T), RS1001730121 (1:6463608 C>A), RS1001781995 (1:6465608 C>T), RS1002062323 (1:6464904 A>C), RS1002179475 (1:6460315 C>T), RS1002377389 (1:6460533 G>A), RS1002983447 (1:6460905 G>A), RS1003183687 (1:6461530 C>A,G), RS1003700326 (1:6467063 G>T), RS1003700687 (1:6465985 G>A,C), RS1003909455 (1:6466507 A>G), RS1004216535 (1:6464864 A>C), RS1004528711 (1:6460577 G>T), RS1004561135 (1:6460682 T>C)

Disease associations

OMIM: gene MIM:603366 | disease phenotypes: MIM:611067

GenCC curated gene-disease

Mondo (1): neuronopathy, distal hereditary motor, autosomal recessive 4 (MONDO:0012608)

Orphanet (1): Autosomal recessive lower motor neuron disease with childhood onset (Orphanet:206580)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567023	Spinal Muscular Atrophy, Distal, Autosomal Recessive, 4 (supp.)

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 — Tumour necrosis factor (TNF) receptor family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	6
bisphenol A	decreases expression, increases expression, increases methylation	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
dioscin	increases expression	2
Arsenic Trioxide	decreases expression	2
Arsenic	increases expression, affects cotreatment, decreases expression, increases abundance	2
Estradiol	increases expression, decreases expression	2
Genistein	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
thymoquinone	decreases reaction, increases expression	1
propylparaben	increases expression	1
methylselenic acid	increases expression	1
morin	increases expression	1
potassium perchlorate	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
VX-agent	increases expression	1
terbufos	increases methylation	1
beta-lapachone	increases expression	1
3,3’-diindolylmethane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
2,5-dimethyl-4-benzoquinone	decreases reaction, increases expression	1
manganese chloride	increases expression	1
saikosaponin D	increases expression	1
potassium chromate(VI)	increases expression	1
phenylbenzoquinone	decreases reaction, increases expression	1
oxophenylarsine	increases expression, increases reaction	1
nickel sulfate	increases expression	1
hydroquinone	decreases expression	1
2-tert-butyl-4-quinone	decreases reaction, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E4IQ	Genomeditech Jurkat H_TNFRSF25(DR3) Reporter	Cancer cell line	Male
CVCL_E7H8	HT29-DR3	Cancer cell line	Female

Clinical trials (associated diseases)

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