TNFRSF13C

Summary

TNFRSF13C (TNF receptor superfamily member 13C, HGNC:17755) is a protein-coding gene on chromosome 22q13.2, encoding Tumor necrosis factor receptor superfamily member 13C (Q96RJ3). B-cell receptor specific for TNFSF13B/TALL1/BAFF/BLyS.

B cell-activating factor (BAFF) enhances B-cell survival in vitro and is a regulator of the peripheral B-cell population. Overexpression of Baff in mice results in mature B-cell hyperplasia and symptoms of systemic lupus erythematosus (SLE). Also, some SLE patients have increased levels of BAFF in serum. Therefore, it has been proposed that abnormally high levels of BAFF may contribute to the pathogenesis of autoimmune diseases by enhancing the survival of autoreactive B cells. The protein encoded by this gene is a receptor for BAFF and is a type III transmembrane protein containing a single extracellular cysteine-rich domain. It is thought that this receptor is the principal receptor required for BAFF-mediated mature B-cell survival.

Source: NCBI Gene 115650 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency, common variable, 4 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 100 total — 1 pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_052945

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17755
Approved symbol	TNFRSF13C
Name	TNF receptor superfamily member 13C
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	BAFFR, CD268
Ensembl gene	ENSG00000159958
Ensembl biotype	protein_coding
OMIM	606269
Entrez	115650

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000291232, ENST00000898406

RefSeq mRNA: 1 — MANE Select: NM_052945 NM_052945

CCDS: CCDS14024

Canonical transcript exons

ENST00000291232 — 3 exons

Exon	Start	End
ENSE00001048605	41926101	41926331
ENSE00001175504	41926638	41926806
ENSE00002600363	41922032	41925554

Expression profiles

Bgee: expression breadth ubiquitous, 151 present calls, max score 91.08.

FANTOM5 (CAGE): breadth broad, TPM avg 6.7157 / max 1409.9791, expressed in 339 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194393	6.5892	327
194391	0.0640	30
194392	0.0626	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	91.08	gold quality
lymph node	UBERON:0000029	86.55	gold quality
vermiform appendix	UBERON:0001154	85.03	gold quality
bone marrow cell	CL:0002092	83.28	gold quality
granulocyte	CL:0000094	79.86	gold quality
caecum	UBERON:0001153	77.41	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.87	silver quality
blood	UBERON:0000178	74.24	gold quality
tonsil	UBERON:0002372	72.01	gold quality
small intestine	UBERON:0002108	71.72	gold quality
ventricular zone	UBERON:0003053	69.21	gold quality
bone marrow	UBERON:0002371	69.08	gold quality
mucosa of transverse colon	UBERON:0004991	68.37	gold quality
colonic epithelium	UBERON:0000397	68.33	gold quality
ganglionic eminence	UBERON:0004023	65.96	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.77	gold quality
skin of leg	UBERON:0001511	65.70	gold quality
buccal mucosa cell	CL:0002336	64.78	silver quality
skin of abdomen	UBERON:0001416	62.09	gold quality
zone of skin	UBERON:0000014	61.60	gold quality
epithelium of nasopharynx	UBERON:0001951	61.49	gold quality
rectum	UBERON:0001052	60.98	gold quality
gall bladder	UBERON:0002110	60.75	gold quality
minor salivary gland	UBERON:0001830	60.69	gold quality
left adrenal gland	UBERON:0001234	60.11	gold quality
mouth mucosa	UBERON:0003729	60.08	gold quality
stromal cell of endometrium	CL:0002255	59.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	59.90	gold quality
left adrenal gland cortex	UBERON:0035825	59.79	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	717.44
E-MTAB-9221	yes	536.14
E-GEOD-110499	yes	216.04
E-HCAD-4	yes	128.30
E-CURD-122	yes	97.33
E-CURD-88	yes	63.63
E-MTAB-9467	yes	44.12
E-ANND-3	yes	41.53
E-CURD-112	yes	13.88
E-MTAB-9543	yes	13.12
E-MTAB-9801	yes	6.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, NFKB1, NFKB, RELA

miRNA regulators (miRDB)

16 targeting TNFRSF13C, 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-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-4710	98.61	65.96	1048

Literature-anchored findings (GeneRIF, showing 40)

• BAFF-R is a receptor for the TNF family member ligand, BAFF [review] (PMID:12456020)
• BAFFR-mediated NF-kappa B activation and IL-10 production in B cells is downregulated by TNFR-associated factor-3. (PMID:12471121)
• crystal structure and interaction with BAFF protein (PMID:12715002)
• BAFF/BLyS receptor 3 comprises a minimal TNF receptor-like module that encodes a highly focused ligand-binding site. (PMID:12755599)
• Expression of BCMA, TACI, and BAFF-R by multiple myeloma cells support cell growth and survival. (PMID:14512299)
• This study reports the crystal structure of a 24-residue fragment of the cytoplasmic portion of BAFF-R bound in complex with TRAF3. (PMID:15585864)
• the PVPAT sequence of BAFFR not only functions as a key signaling motif of BAFFR but also determines its signaling specificity in the induction of the noncanonical NF-kappaB pathway (PMID:15644327)
• amino acid sequence of genomic DNA from blood of common variable immunodeficiency patients;mutations may result in humoral immunodeficiency (PMID:16160919)
• BAFF-R is expressed on most mature B cells and B-cell lymphoproliferative disorders. (PMID:16226112)
• BAFF-R is consistently occupied on blood B cells in systemic lupus erythematosus (PMID:16320342)
• Detection in lymphoma tissue biopsies may be of clinical relevance in predicting response to treatment. (PMID:16769579)
• BR3, which is expressed on all mature B cells, is a specific receptor for the B-cell survival and maturation factor BAFF. (PMID:16840730)
• Review. The splice variants, binding specificities, structural determinants for ligand selectivity, and signaling pathways are reviewed. (PMID:16914324)
• Review. BLyS signaling via BR3 is the dominant homeostatic regulator of primary B cell pools. (PMID:16919470)
• Review. BAFF and its receptor have roles in B cell biology outside of a survival mechanism. These include germinal center maintenance, isotype switching, and regulation of specific B cell surface markers. (PMID:16931038)
• Review. Direct BAFF/APRIL signalling in T cells and/or T cell modulation in response to a BAFF-modified B cell compartment may play an important role in inflammation and immunomodulation. (PMID:16931039)
• recombinant gelonin/B lymphocyte stimulator fusion toxin may have potential therapeutic efficacy for B-CLL patients (PMID:17119117)
• BAFF-R and CD40 enhance B cell responsiveness to transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI)-mediated suppression. (PMID:17154264)
• Widely expressed in the synovial tissue of patients with rheumatoid arthritis. (PMID:17963166)
• The BAFF-binding receptor profile may serve as a footprint of the activation history and stage of differentiation of normal human B cells. (PMID:18025170)
• Of 9 CVID patients…No mutations of SAP, ICOS, TACI, BAFFR, and CD19 were identified (PMID:18051214)
• We propose that an aberrant BAFF/BAFF-R-dependent autocrine mechanism may play a role in the development of certain types of nonhematopoietic cancer cells. (PMID:18775026)
• the assessment of expression of BAFF-binding receptors aids subclassification and prognostication of DLBCL (PMID:19207947)
• deletion of the BAFF-R gene in humans causes a characteristic immunological phenotype but it does not necessarily lead to a clinically manifest immunodeficiency (PMID:19666484)
• molecular mechanisms underlying this crosstalk between B cell receptor and BAFF receptor signaling that maintain B cell survival and metabolic fitness (PMID:19726767)
• BLyS and its receptors might have a potential role in the growth and survival of malignant plasma cells. (PMID:19731825)
• the mechanism of transcriptional regulation of BAFF-R (PMID:20025535)
• IFN-gamma and the NF-kappaB pathway could be involved in regulating the transcription and mRNA expression of BAFF-R gene. (PMID:20230666)
• This report is the first showing universal expression of BAFF-R by pre-B ALL cells. (PMID:20460528)
• Data from BAFF-R-expressing cells suggested potential regulatory sites in TNFRSF13C promoter region. (PMID:20554963)
• inverse correlation between BAFF and APRIL in Kawasaki disease is reversed by IVIG treatment (PMID:20945608)
• Elevated plasma BAFF and reduced BAFF receptor 3 (BR3) protein expression on peripheral B cells could act as biomarkers for active disease in systemic lupus erythematosus patients (PMID:20974656)
• a novel lymphoma-associated mutation in human BAFF-R that results in NF-kappaB activation and reveals TRAF6 as a necessary component of normal BAFF-R signaling. (PMID:21041452)
• Results describe the mechanisms underlying aberrant BAFF-R expression in precursor B acute lymphoblastic leukemia (precursor B-ALL) and mature B chronic lymphocytic leukemia (CLL). (PMID:21099364)
• BAFF-R was rather specifically related to low growth activity of germinal center B-cell-like -type diffuse large B-cell lymphoma of nodal origin. (PMID:21123970)
• This is the first study, presenting together the TNFSF members APRIL, BAFF, TWEAK and their receptors in different areas of normal renal tissue and renal cell carcinoma. (PMID:21483105)
• reduced expression via inhibition of the NF-KappaB pathway in B cells of rheumatoid arthritis patients (PMID:21515993)
• It was also found that NF-kappaB was an important transcription factor involved in regulating BAFF-R expression through one NF-kappaB binding site in the BAFF-R promoter (PMID:21607696)
• primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI (PMID:21687682)
• The human BAFF-R gene might be regulated via a transcriptional event through one putative NF-kappaB site on the BAFF-R gene promoter. (PMID:21744373)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnfrsf13c	ENSMUSG00000068105
rattus_norvegicus	Tnfrsf13c	ENSRNOG00000007664

Paralogs (1): TNFRSF17 (ENSG00000048462)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 13C — Q96RJ3 (reviewed: Q96RJ3)

Alternative names: B-cell-activating factor receptor, BAFF receptor, BLyS receptor 3

All UniProt accessions (2): Q96RJ3, Q5H8V1

UniProt curated annotations — full annotation on UniProt →

Function. B-cell receptor specific for TNFSF13B/TALL1/BAFF/BLyS. Promotes the survival of mature B-cells and the B-cell response.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in spleen and lymph node, and in resting B-cells. Detected at lower levels in activated B-cells, resting CD4+ T-cells, in thymus and peripheral blood leukocytes.

Disease relevance. Immunodeficiency, common variable, 4 (CVID4) [MIM:613494] A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96RJ3-1	1	yes
Q96RJ3-2	2

RefSeq proteins (1): NP_443177* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015336	TNFR_13C_TALL-1-bd	Domain
IPR022338	TNFR_13C	Family
IPR043521	TNFR_13C/17	Family

Pfam: PF09256

UniProt features (24 total): mutagenesis site 4, sequence variant 3, region of interest 3, topological domain 2, disulfide bond 2, strand 2, compositionally biased region 2, chain 1, splice variant 1, transmembrane region 1, turn 1, helix 1, repeat 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
1OQE	X-RAY DIFFRACTION	2.5
8ZUJ	ELECTRON MICROSCOPY	2.58
2HFG	X-RAY DIFFRACTION	2.61
8ZUK	ELECTRON MICROSCOPY	2.83
3V56	X-RAY DIFFRACTION	3
4V46	X-RAY DIFFRACTION	3.3
1MPV	SOLUTION NMR
1OSX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RJ3-F1	63.90	0.14

Antibody-complex structures (SAbDab): 1 — 2HFG

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 (2): 19–32, 24–35

Mutagenesis-validated functional residues (4):

Position	Phenotype
24	abolishes a disulfide bond and thereby changes the specificity, so that both tnfsf13b and tnfsf13 can be bound.
26	strongly reduced affinity for tnfsf13b.
28	strongly reduced affinity for tnfsf13b.
35	abolishes a disulfide bond and thereby changes the specificity, so that both tnfsf13b and tnfsf13 can be bound.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-5676594	TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway

MSigDB gene sets: 214 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_LYMPHOCYTE_COSTIMULATION, MODULE_317, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, AREB6_01, GOBP_POSITIVE_REGULATION_OF_B_CELL_PROLIFERATION, GGGTGGRR_PAX4_03, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION

GO Biological Process (7): adaptive immune response (GO:0002250), positive regulation of B cell proliferation (GO:0030890), T cell costimulation (GO:0031295), B cell costimulation (GO:0031296), tumor necrosis factor-mediated signaling pathway (GO:0033209), positive regulation of T cell proliferation (GO:0042102), immune system process (GO:0002376)

GO Molecular Function (1): signaling receptor activity (GO:0038023)

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
Cytokine Signaling in Immune system	1
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of lymphocyte proliferation	2
positive regulation of B cell activation	2
lymphocyte costimulation	2
positive regulation of T cell activation	2
immune response	1
regulation of B cell proliferation	1
B cell proliferation	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
T cell proliferation	1
regulation of T cell proliferation	1
biological_process	1
molecular transducer activity	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1416 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF13C	TNFSF13B	Q9Y275	999
TNFRSF13C	TNFRSF13B	O14836	987
TNFRSF13C	CD40	P25942	968
TNFRSF13C	TNFSF13	O75888	951
TNFRSF13C	TNFRSF17	Q02223	942
TNFRSF13C	LTBR	P36941	937
TNFRSF13C	CD40LG	P29965	921
TNFRSF13C	TRAF3	Q13114	896
TNFRSF13C	NFKB2	Q00653	831
TNFRSF13C	CD19	P15391	799
TNFRSF13C	CAMLG	P49069	783
TNFRSF13C	MAP3K14	Q99558	761
TNFRSF13C	CD27	P26842	753
TNFRSF13C	CES3	Q6UWW8	743
TNFRSF13C	TNF	P01375	742

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TNFSF13B	TNFRSF13C	psi-mi:“MI:0407”(direct interaction)	0.440
LILRB2	TNFRSF13C	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF13C	LILRB2	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF13C	TNPO2	psi-mi:“MI:0914”(association)	0.350
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): TNFRSF13C (Co-crystal Structure), MTCH2 (Affinity Capture-MS), MCU (Affinity Capture-MS), GLMN (Affinity Capture-MS), TNPO2 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), TNFRSF13C (Co-crystal Structure), TNFRSF13C (Reconstituted Complex), TNFRSF13C (Co-fractionation), TNFRSF13C (Co-fractionation), TNFRSF13C (Co-fractionation), TNFRSF13C (Affinity Capture-Western), TRAF1 (Affinity Capture-Western), TRAF3 (Affinity Capture-Western)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A286YF58, A0A2R8YCJ5, A0A7I2V3R4, A2A699, A2VDX9, A6NCS6, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NLJ0, A8MVW0, B2RU40, B7Z1M9, B8ZZ34, C9JH25, C9JVW0, D4A9R4, J3QNX5, M0QZC1, P03971, P0CG09, P0DPE3, Q0PHV7, Q0VD38, Q14761, Q29RK8, Q29RM6, Q2KJ18, Q2M3G4, Q2M3V2, Q5T442, Q64697, Q69YZ2, Q6F5E0, Q6NY19, Q6UXK2, Q80XF7

Diamond homologs: Q96RJ3, Q9D8D0

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
TNFSF13B	“up-regulates activity”	TNFRSF13C	binding
TNFRSF13C	“down-regulates quantity by destabilization”	TRAF3	binding
TNFRSF13C	up-regulates	B_cell_maturation
TNFRSF13C	up-regulates	Lymphoma

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	52
Likely benign	30
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4459	NM_052945.4(TNFRSF13C):c.265_288del (p.Leu89_Val96del)	Pathogenic

SpliceAI

340 predictions. Top by Δscore:

Variant	Effect	Δscore
22:41925362:C:CA	donor_gain	0.9900
22:41926099:ACCGT:A	donor_gain	0.9900
22:41926100:CCGTC:C	donor_gain	0.9900
22:41926096:CTCA:C	donor_loss	0.9800
22:41926097:TCAC:T	donor_loss	0.9800
22:41926098:CAC:C	donor_loss	0.9800
22:41926099:ACCG:A	donor_loss	0.9800
22:41926100:C:CT	donor_loss	0.9800
22:41926100:CCGT:C	donor_gain	0.9800
22:41926103:T:TA	donor_gain	0.9800
22:41926091:CGGAA:C	donor_gain	0.9700
22:41926099:A:AC	donor_gain	0.9700
22:41926100:C:CC	donor_gain	0.9700
22:41926636:AC:A	donor_gain	0.9700
22:41926637:CC:C	donor_gain	0.9700
22:41926632:CCTTA:C	donor_loss	0.9500
22:41926633:CTTA:C	donor_loss	0.9500
22:41926634:TTAC:T	donor_loss	0.9500
22:41926635:TACCC:T	donor_loss	0.9500
22:41926636:A:C	donor_loss	0.9500
22:41926093:GAACT:G	donor_loss	0.9400
22:41926099:AC:A	donor_gain	0.9300
22:41926100:CC:C	donor_gain	0.9300
22:41926631:CCCTT:C	donor_loss	0.9300
22:41926100:CCG:C	donor_gain	0.9100
22:41925351:T:TA	donor_gain	0.8700
22:41925141:C:CT	donor_gain	0.8600
22:41926636:A:AC	donor_gain	0.8500
22:41926637:C:CC	donor_gain	0.8500
22:41925142:C:CT	donor_gain	0.8200

AlphaMissense

1129 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:41925391:C:A	K177N	0.994
22:41925391:C:G	K177N	0.994
22:41925404:A:G	L173P	0.992
22:41926699:G:C	F25L	0.987
22:41926699:G:T	F25L	0.987
22:41926701:A:G	F25L	0.987
22:41925417:C:G	G169R	0.985
22:41926679:C:T	C32Y	0.984
22:41925395:G:A	T176I	0.983
22:41925425:G:A	T166I	0.982
22:41926697:T:A	D26V	0.982
22:41926703:C:G	C24S	0.981
22:41926704:A:T	C24S	0.981
22:41925404:A:T	L173Q	0.980
22:41926212:C:G	G86R	0.980
22:41926702:G:C	C24W	0.978
22:41925398:G:A	T175I	0.977
22:41926678:G:C	C32W	0.976
22:41926704:A:G	C24R	0.976
22:41925395:G:T	T176N	0.975
22:41925417:C:A	G169C	0.975
22:41925419:A:G	L168P	0.975
22:41925428:G:T	A165D	0.975
22:41926670:C:T	C35Y	0.974
22:41925402:C:T	V174M	0.973
22:41925423:C:T	E167K	0.973
22:41926697:T:C	D26G	0.973
22:41925421:C:A	E167D	0.972
22:41925421:C:G	E167D	0.972
22:41925398:G:T	T175N	0.971

dbSNP variants (sampled 300 via entrez): RS1000003454 (22:41928787 G>A), RS1000160835 (22:41923554 TG>T,TGG), RS1000232273 (22:41923291 T>G), RS1000439692 (22:41928609 G>T), RS1000780087 (22:41925209 G>A), RS1000961266 (22:41925491 G>A), RS1001080917 (22:41927355 C>T), RS1001407710 (22:41927569 G>A), RS1002011994 (22:41926356 G>C), RS1002465968 (22:41925779 G>A), RS1002488801 (22:41926173 C>G), RS1002786410 (22:41922140 T>A), RS1002978347 (22:41922376 G>A,C), RS1003083134 (22:41924955 A>C), RS1003280066 (22:41926581 C>A,T)

Disease associations

OMIM: gene MIM:606269 | disease phenotypes: MIM:613494

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency, common variable, 4	Moderate	Autosomal recessive
common variable immunodeficiency	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency, common variable, 4	Limited	AR

Mondo (2): immunodeficiency, common variable, 4 (MONDO:0013284), common variable immunodeficiency (MONDO:0015517)

Orphanet (2): OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Adult-onset common variable immunodeficiency due to BAFF-receptor deficiency (Orphanet:696925)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0000509	Conjunctivitis
HP:0001287	Meningitis
HP:0001744	Splenomegaly
HP:0002014	Diarrhea
HP:0002110	Bronchiectasis
HP:0002240	Hepatomegaly
HP:0002664	Neoplasm
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002729	Follicular hyperplasia
HP:0002837	Recurrent bronchitis
HP:0002850	Decreased circulating total IgM
HP:0002960	Autoimmunity
HP:0003581	Adult onset
HP:0004315	Decreased circulating IgG concentration
HP:0005387	Combined immunodeficiency
HP:0006532	Recurrent pneumonia
HP:0011108	Recurrent sinusitis
HP:0011839	Abnormal total T cell count
HP:0011840	Abnormal T cell physiology
HP:0410300	Complete or near-complete absence of specific antibody response to unconjugated pneumococcus vaccine
HP:0410301	Partial absence of specific antibody response to unconjugated pneumococcus vaccine

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002539_95	Schizophrenia	2.000000e-09
GCST006803_13	Schizophrenia	2.000000e-14
GCST010132_1	Processed meat consumption	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630882 (SINGLE PROTEIN)

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

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
ianalumab	Antagonist	10.72	pIC50

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Allergens	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
sodium arsenite	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Erythrosine	affects binding, decreases reaction	1
Rose Bengal	affects binding, decreases reaction	1
Gold Compounds	increases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8XB	Ubigene HCT 116 TNFRSF13C KO	Cancer cell line	Male
CVCL_D9UK	Ubigene HEK293 TNFRSF13C KO	Transformed cell line	Female
CVCL_FA30	COS-1/B2T.cl.17	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	PHASE4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	PHASE4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT00168012	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00322556	PHASE3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00542997	PHASE3	COMPLETED	Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy
NCT01884311	PHASE3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases
NCT01963143	PHASE3	COMPLETED	Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases
NCT02247141	PHASE3	COMPLETED	A Multi-centre Open Study to Assess the Safety and Efficacy of Subgam®
NCT01489618	PHASE2	TERMINATED	Prime Boost Vaccination Strategy Combining Conjugated Anti- Pneumococcal Vaccine (s0) and Polysaccharide Anti- Pneumococcal Vaccine (s4) Compared to Polysaccharide Anti- Pneumococcal Vaccine Alone (s4) In Patients With Common Variable Immunodeficiency
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02579967	PHASE2	RECRUITING	Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
NCT03663933	PHASE2	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
NCT04339777	PHASE2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
NCT04925375	PHASE2	RECRUITING	Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease
NCT05593588	PHASE2	ENROLLING_BY_INVITATION	Senolytics Treatment of Interstitial Lung Disease in Common Variable Immunodeficiency
NCT06897358	PHASE2	ACTIVE_NOT_RECRUITING	Leniolisib for Immune Dysregulation in CVID
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00263237	PHASE1	COMPLETED	STA-5326 Meslylate to Treat Gut Inflammation Associated With Common Variable Immunodeficiency
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT00004695	Not specified	COMPLETED	Randomized Study of Polyethylene-Glycol-Conjugated Interleukin 2 in Patients With Common Variable Immunodeficiency
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00015431	Not specified	COMPLETED	Immune System and Gut Abnormalities in Patients With Common Variable Immunodeficiency With and Without Gastrointestinal Symptoms
NCT00661401	Not specified	COMPLETED	Specific IgG Antibody in Patients With Primary Antibody Deficiencies Treated With Subcutaneous Immunoglobulin
NCT00943514	Not specified	RECRUITING	Natural History of Bronchiectasis
NCT01196702	Not specified	COMPLETED	Lymphocyte Immunophenotyping in Common Variable Immunodeficiency
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01981785	Not specified	UNKNOWN	Investigation of Immune Disorders and Deficiencies
NCT02960399	Not specified	TERMINATED	Assessment of Immunogenicity of Zostavax® in Patients With Antibody Deficiency 60 Years of Age and Older
NCT03188419	Not specified	COMPLETED	Breadth of Donor Options for People With Inherited Diseases Requiring Allogeneic Hematopoietic Stem Cell Transplant in the Era of Alternative Donor Transplants Using Post-Transplantation Cyclophosphamide
NCT03211689	Not specified	COMPLETED	The Impact of Exercise on Stress, Fatigue, and Quality of Life in Individuals With Primary Immunodeficiency Disease
NCT03534479	Not specified	COMPLETED	Human IgGs and Endothelial Function in Vivo in Humans
NCT05310604	Not specified	COMPLETED	Early Detection of Primary Antibody Deficiencies in Primary Care Facilities by an Algorithm Driven Selection of Serologic Testing in Individuals at Risk.
NCT05321407	Not specified	ACTIVE_NOT_RECRUITING	COVID-19 Vaccine Responses in PIDD Subjects
NCT05481554	Not specified	UNKNOWN	Composition and Function of Gut Microbiota in Porto-sinusoidal Vascular Disease Associated With Variable Common Immunodeficiency
NCT06145100	Not specified	COMPLETED	Prediction of Portal Hypertension in Patients With CVID (CVID-pHT)