TNFRSF13B

Summary

TNFRSF13B (TNF receptor superfamily member 13B, HGNC:18153) is a protein-coding gene on chromosome 17p11.2, encoding Tumor necrosis factor receptor superfamily member 13B (O14836). Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity.

The protein encoded by this gene is a lymphocyte-specific member of the tumor necrosis factor (TNF) receptor superfamily. It interacts with calcium-modulator and cyclophilin ligand (CAML). The protein induces activation of the transcription factors NFAT, AP1, and NF-kappa-B and plays a crucial role in humoral immunity by interacting with a TNF ligand. This gene is located within the Smith-Magenis syndrome region on chromosome 17.

Source: NCBI Gene 23495 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency, common variable, 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 54
• Clinical variants (ClinVar): 390 total — 27 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 28
• MANE Select transcript: NM_012452

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18153
Approved symbol	TNFRSF13B
Name	TNF receptor superfamily member 13B
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	TACI, CD267, IGAD2
Ensembl gene	ENSG00000240505
Ensembl biotype	protein_coding
OMIM	604907
Entrez	23495

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000261652, ENST00000579009, ENST00000579315, ENST00000581616, ENST00000582931, ENST00000583789, ENST00000584950

RefSeq mRNA: 1 — MANE Select: NM_012452 NM_012452

CCDS: CCDS11181

Canonical transcript exons

ENST00000261652 — 5 exons

Exon	Start	End
ENSE00000691547	16940326	16940511
ENSE00001323387	16939081	16939797
ENSE00002718187	16972015	16972118
ENSE00003577601	16948738	16948983
ENSE00003659018	16952446	16952583

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 90.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9604 / max 329.8356, expressed in 86 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164744	1.9604	86

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	90.91	gold quality
olfactory bulb	UBERON:0002264	89.73	gold quality
spleen	UBERON:0002106	89.34	gold quality
apex of heart	UBERON:0002098	88.82	gold quality
gluteal muscle	UBERON:0002000	88.00	silver quality
triceps brachii	UBERON:0001509	87.42	gold quality
cervix squamous epithelium	UBERON:0006922	87.19	gold quality
lymph node	UBERON:0000029	85.70	gold quality
tongue squamous epithelium	UBERON:0006919	84.81	gold quality
buccal mucosa cell	CL:0002336	83.68	gold quality
tendon of biceps brachii	UBERON:0008188	83.37	gold quality
orbitofrontal cortex	UBERON:0004167	83.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.75	gold quality
epithelial cell of pancreas	CL:0000083	81.50	gold quality
bone marrow cell	CL:0002092	79.85	gold quality
gastrocnemius	UBERON:0001388	79.81	gold quality
caecum	UBERON:0001153	79.53	gold quality
vermiform appendix	UBERON:0001154	79.27	gold quality
muscle of leg	UBERON:0001383	79.20	gold quality
pancreatic ductal cell	CL:0002079	78.45	silver quality
parotid gland	UBERON:0001831	77.89	silver quality
muscle organ	UBERON:0001630	77.71	gold quality
Brodmann (1909) area 46	UBERON:0006483	77.66	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	77.63	gold quality
pylorus	UBERON:0001166	76.35	silver quality
heart left ventricle	UBERON:0002084	75.73	gold quality
cardiac ventricle	UBERON:0002082	75.56	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.54	gold quality
vena cava	UBERON:0004087	75.22	gold quality
right atrium auricular region	UBERON:0006631	75.19	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	110.87
E-CURD-88	yes	82.60
E-MTAB-9467	yes	51.40
E-HCAD-4	yes	49.90
E-MTAB-8410	yes	31.82
E-HCAD-11	yes	20.99
E-MTAB-10553	yes	11.01
E-ANND-3	yes	10.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NCOR1

miRNA regulators (miRDB)

35 targeting TNFRSF13B, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-6895-3P	98.79	65.69	996
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-6867-3P	98.12	66.07	1305
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-4723-3P	97.67	65.91	1017
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255

Literature-anchored findings (GeneRIF, showing 40)

• Expression of BCMA, TACI, and BAFF-R by multiple myeloma cells support cell growth and survival. (PMID:14512299)
• another form of TACI exists wherein the N-terminal cysteine-rich domain (CRD) is removed by alternative splicing and is capable of ligand-induced cell signaling and that the second CRD alone (TACI_d2) contains full affinity for both APRIL and BAFF (PMID:15542592)
• TACI(hi) myeloma cells displayed a mature plasma cell gene signature, indicating dependence on the BM environment. In contrast, the TACI(lo) group had a gene signature of plasmablasts, suggesting an attenuated dependence on the BM environment (PMID:15827134)
• 4 of 19 unrelated individuals with common variable immunodeficiency and 1 of 16 individuals with IgA deficiency had a missense mutation in one allele of TNFRSF13B (PMID:16007086)
• identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency (PMID:16007087)
• Review. The splice variants, binding specificities, structural determinants for ligand selectivity, and signaling pathways are reviewed. (PMID:16914324)
• Review. Short-lived antibody forming cell populations and their proliferating progenitors express a TACI-predominant signature. (PMID:16919470)
• 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)
• The TACI inhibited HRS cell accumulation in vitro and might attenuate HL expansion in vivo. (PMID:16960154)
• simultaneous binding of TACI and HSPG on B cells with APRIL is crucial for IgA production (PMID:17119122)
• TACI-specific signaling inhibits both B cell activating factor of the TNF family receptor (BAFF-R) and CD40-enhanced antibody production from peripheral blood B cells in vitro, although TACI-specific signaling directly induces mild B cell apoptosis. (PMID:17154264)
• This review defines the exact contribution of TACI receptor stimulation by specific triggers in vitro, enabling us to better understand the complex, context-dependent responses initiated by TACI in vivo. (PMID:17171762)
• Role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. (PMID:17392797)
• Role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. (PMID:17392798)
• We analyzed TACI in humans with SLE and found 4 variants: R20C in exon 1, R72H in exon 3, the silent variation c.327 G > A in exon 3, and A181E in exon 4. No significant association of SLE with any of these variants was found. (PMID:17464555)
• TACI preassembles as an oligomeric complex prior to ligand binding (PMID:17492055)
• TACI activation can upregulate c-maf expression which, in turn, controls cyclin D2, and integrin beta7 gene expression in human myeloma cell lines (PMID:17550853)
• These results suggest that TACI mutations can lead to CVID. (PMID:17917015)
• Mutations in TACI significantly predispose to autoimmunity and lymphoid hyperplasia in common variable immunodeficiency. (PMID:17983875)
• The TACI is inducible early upon B cell activation and this is independent of B cell turnover, and TACI expression requires activation of the ERK1/2 pathway. (PMID:18025170)
• APRIL plays an essential role in the survival of TACI(high) bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment (PMID:18046446)
• Of 9 CVID patients…No mutations of SAP, ICOS, TACI, BAFFR, and CD19 were identified (PMID:18051214)
• mutated in nearly 10% of patients with common variable immune deficiency (PMID:18978466)
• C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation. (PMID:18981294)
• BLyS protein concentration and BLyS, TACI and BAFF-R mRNA expression levels were significantly elevated in patients with multiple myeloma. (PMID:19028483)
• There was a variable pattern of expression of TACI amongst the different types of B-cell lymphomas (PMID:19207947)
• TNFRSF13B mutations induce disease susceptibility rather than cause common variable immunodeficiency directly (PMID:19210517)
• overexpression in multiple myeloma and thyroid carcinoma; association with poor prognosis in lymphoma (PMID:19291294)
• role for APRIL-TACI-specific signaling in follicular lymphoma B-cell growth (PMID:19321861)
• our work seems to discard a role of TNFRSF13B mutations in IgA Deficiency, concordantly with the most recent published studies. (PMID:19392801)
• syndecan-1 is a co-receptor for APRIL and TACI at the cell surface of MMC, promoting the activation of an APRIL/TACI pathway that induces survival and proliferation in multiple myeloma cells (PMID:19456850)
• Single Nucleotide Polymorphisms in TNFRSF13B is associated with common variable immunodeficiency. (PMID:19494827)
• mTACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions. (PMID:19605846)
• novel mutations identified in this study support the notion of a crucial role for TACI in B cell differentiation (PMID:19629655)
• we observed APRIL expression, together with TACI and BCMA in gut-associated lymphoid tissue, lamina propria, and in the epithelium of stomach, small and large intestine, and rectum. (PMID:19741596)
• TACI mutations are unlikely to play a critical role in creating susceptibility to CVID among patients with previously recognized MHC class I and class II susceptibility alleles (PMID:19775471)
• the TNFRSF13B A181E mutation is associated with a very heterogeneous clinical presentation along with variability in B-cell numbers and amount of TACI protein on memory B cells in Common Variable ImmunoDeficiency (PMID:20156508)
• MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification (PMID:20676093)
• mutations result in impaired B cell response through haploinsufficiency (PMID:20889194)
• TACI expression on CD19+ B cells was up-regulated in patients with lupus nephritis (PMID:20974656)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tnfrsf13b	ENSMUSG00000010142
rattus_norvegicus	Tnfrsf13b	ENSRNOG00000063438

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 13B — O14836 (reviewed: O14836)

Alternative names: Transmembrane activator and CAML interactor

All UniProt accessions (4): E7ER05, J3QR67, O14836, Q4ACX1

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity. Mediates calcineurin-dependent activation of NF-AT, as well as activation of NF-kappa-B and AP-1. Involved in the stimulation of B- and T-cell function and the regulation of humoral immunity.

Subunit / interactions. Binds TRAF2, TRAF5 and TRAF6. Binds the NH2-terminal domain of CAMLG with its C-terminus.

Subcellular location. Membrane.

Tissue specificity. Highly expressed in spleen, thymus, small intestine and peripheral blood leukocytes. Expressed in resting B-cells and activated T-cells, but not in resting T-cells.

Disease relevance. Immunodeficiency, common variable, 2 (CVID2) [MIM:240500] 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. Immunoglobulin A deficiency 2 (IGAD2) [MIM:609529] Selective deficiency of immunoglobulin A (IGAD) is the most common form of primary immunodeficiency, with an incidence of approximately 1 in 600 individuals in the western world. Individuals with symptomatic IGAD often have deficiency of IgG subclasses or decreased antibody response to carbohydrate antigens such as pneumococcal polysaccharide vaccine. Individuals with IGAD also suffer from recurrent sinopulmonary and gastrointestinal infections and have an increased incidence of autoimmune disorders and of lymphoid and non-lymphoid malignancies. In vitro studies have suggested that some individuals with IGAD have impaired isotype class switching to IgA and others may have a post-switch defect. IGAD and CVID have been known to coexist in families. Some individuals initially present with IGAD1 and then develop CVID. These observations suggest that some cases of IGAD and CVID may have a common etiology. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
O14836-1	1	yes
O14836-2	2
O14836-3	3

RefSeq proteins (1): NP_036584* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015384	TACI_Cys-rich-dom	Domain
IPR022317	TNFR_13B	Family

Pfam: PF09305

UniProt features (31 total): disulfide bond 6, sequence variant 5, helix 4, splice variant 3, topological domain 2, strand 2, repeat 2, region of interest 2, chain 1, transmembrane region 1, turn 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1XU1	X-RAY DIFFRACTION	1.9
1XUT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14836-F1	62.65	0.12

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 (6): 34–47, 50–62, 54–66, 71–86, 89–100, 93–104

Glycosylation sites (1): 128

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 276 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_B_CELL_HOMEOSTASIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, MODULE_45, MODULE_64, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_NEGATIVE_REGULATION_OF_B_CELL_ACTIVATION, GOBP_B_CELL_PROLIFERATION, GUTIERREZ_WALDENSTROEMS_MACROGLOBULINEMIA_1_DN, MODULE_75, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (6): B cell homeostasis (GO:0001782), hematopoietic progenitor cell differentiation (GO:0002244), adaptive immune response (GO:0002250), cell surface receptor signaling pathway (GO:0007166), negative regulation of B cell proliferation (GO:0030889), immune system process (GO:0002376)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (2): 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
lymphocyte homeostasis	1
hemopoiesis	1
cell differentiation	1
immune response	1
signal transduction	1
regulation of B cell proliferation	1
B cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of B cell activation	1
biological_process	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1220 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF13B	TNFSF13B	Q9Y275	999
TNFRSF13B	CAMLG	P49069	997
TNFRSF13B	TNFSF13	O75888	996
TNFRSF13B	TNFRSF13C	Q96RJ3	987
TNFRSF13B	TNFRSF17	Q02223	959
TNFRSF13B	CD40LG	P29965	937
TNFRSF13B	CD40	P25942	840
TNFRSF13B	ICOS	Q9Y6W8	829
TNFRSF13B	TNF	P01375	817
TNFRSF13B	MYD88	P78397	763
TNFRSF13B	CR2	P20023	758
TNFRSF13B	IFNG	P01579	730
TNFRSF13B	A0A0A6YY99	A0A0A6YY99	700
TNFRSF13B	TRAF6	Q9Y4K3	695
TNFRSF13B	ICOSLG	O75144	681

IntAct

33 interactions, top by confidence:

A	B	Type	Score
TNFSF13B	TNFRSF13B	psi-mi:“MI:0915”(physical association)	0.840
TNFRSF13B	TNFSF13B	psi-mi:“MI:0915”(physical association)	0.840
TNFSF13B	TNFRSF13B	psi-mi:“MI:0407”(direct interaction)	0.840
TNFRSF13B	TNFSF13B	psi-mi:“MI:0407”(direct interaction)	0.840
MYD88	TNFRSF13B	psi-mi:“MI:0915”(physical association)	0.690
TNFRSF13B	MYD88	psi-mi:“MI:0915”(physical association)	0.690
TNFRSF13B	MYD88	psi-mi:“MI:0407”(direct interaction)	0.690
MYD88	TNFRSF13B	psi-mi:“MI:0403”(colocalization)	0.690
TNFRSF13B	TNFSF13	psi-mi:“MI:0915”(physical association)	0.610
TNFRSF13B	TNFSF13	psi-mi:“MI:0407”(direct interaction)	0.610
TNFRSF13B	SGTA	psi-mi:“MI:0915”(physical association)	0.560
TNFRSF13B	TRAF2	psi-mi:“MI:0914”(association)	0.530
TNFRSF13B	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
CAMLG	TNFRSF13B	psi-mi:“MI:0403”(colocalization)	0.510
TNFRSF13B	TRAF5	psi-mi:“MI:0914”(association)	0.460
Tnfsf13	TNFRSF13B	psi-mi:“MI:0407”(direct interaction)	0.440
IRAK4	TNFRSF13B	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF13B	IRAK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): TNFRSF13B (Two-hybrid), SGTA (Two-hybrid), FIZ1 (Affinity Capture-MS), ZNF579 (Affinity Capture-MS), ZNF646 (Affinity Capture-MS), CD70 (Affinity Capture-MS), RBM26 (Affinity Capture-MS), RBM27 (Affinity Capture-MS), ZFP91 (Affinity Capture-MS), RRP1 (Affinity Capture-MS), ZNF638 (Affinity Capture-MS), RBM23 (Affinity Capture-MS), RNF166 (Affinity Capture-MS), TEX10 (Affinity Capture-MS), C1QBP (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GV85, A2ALI5, A2APT9, B0BN44, B1ARY8, B6ZI38, O14836, O35188, O55145, O60279, O60667, P07141, P09603, P0C8S2, P28906, P40225, P40226, P42705, P78423, Q06154, Q08DV9, Q13261, Q1ERP8, Q28270, Q2TB54, Q3UY90, Q4V9H3, Q4W8E7, Q5F267, Q5R770, Q60819, Q64314, Q6PAL1, Q6PCP7, Q6UXB8, Q80XI1, Q8BLK9, Q8CAE9, Q8CBC4, Q8JZQ0

Diamond homologs: O14836, Q9ET35

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TNFSF13	up-regulates	TNFRSF13B	binding
TNFSF13B	up-regulates	TNFRSF13B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 13 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	6	39.6×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	5
Uncertain significance	201
Likely benign	105
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071649	NM_012452.3(TNFRSF13B):c.552C>A (p.Cys184Ter)	Pathogenic
1379832	NM_012452.3(TNFRSF13B):c.62-2A>G	Pathogenic
1401351	NM_012452.3(TNFRSF13B):c.497del (p.Thr166fs)	Pathogenic
1422026	NM_012452.3(TNFRSF13B):c.25C>T (p.Arg9Ter)	Pathogenic
1436172	NM_012452.3(TNFRSF13B):c.61+2T>C	Pathogenic
1456816	NM_012452.3(TNFRSF13B):c.298dup (p.Cys100fs)	Pathogenic
1974800	NM_012452.3(TNFRSF13B):c.306C>A (p.Tyr102Ter)	Pathogenic
2425818	NC_000017.10:g.(?16875309)(16875389_?)del	Pathogenic
265340	NM_012452.3(TNFRSF13B):c.431C>G (p.Ser144Ter)	Pathogenic
2778898	NM_012452.3(TNFRSF13B):c.91_92del (p.Met31fs)	Pathogenic
2780378	NM_012452.3(TNFRSF13B):c.355del (p.Arg119fs)	Pathogenic
3243072	NC_000017.10:g.(?16852032)(16852317_?)del	Pathogenic
3243073	NC_000017.10:g.(?16842861)(16843845_?)del	Pathogenic
3677153	NM_012452.3(TNFRSF13B):c.246_265del (p.Leu83fs)	Pathogenic
3687684	NM_012452.3(TNFRSF13B):c.493_497dup (p.Leu167fs)	Pathogenic
3722490	NM_012452.3(TNFRSF13B):c.306C>G (p.Tyr102Ter)	Pathogenic
4531637	NM_012452.3(TNFRSF13B):c.141C>A (p.Cys47Ter)	Pathogenic
4777067	NM_012452.3(TNFRSF13B):c.452dup (p.Leu153fs)	Pathogenic
5306	NM_012452.2(TNFRSF13B):c.581_582delCCinsAA (p.Ser194Ter)	Pathogenic
5307	NM_012452.3(TNFRSF13B):c.431C>A (p.Ser144Ter)	Pathogenic
647108	NM_012452.3(TNFRSF13B):c.95_96dup (p.Ser33fs)	Pathogenic
647267	NM_012452.3(TNFRSF13B):c.61+1G>T	Pathogenic
657940	NM_012452.3(TNFRSF13B):c.227_231del (p.Gly76fs)	Pathogenic
840923	NM_012452.3(TNFRSF13B):c.198C>A (p.Cys66Ter)	Pathogenic
853184	NM_012452.3(TNFRSF13B):c.62-1G>A	Pathogenic
942527	NM_012452.3(TNFRSF13B):c.61+2T>A	Pathogenic
973680	NM_012452.3(TNFRSF13B):c.350_356del (p.Glu117fs)	Pathogenic
1068411	NC_000017.10:g.(?16842841)(16855917_?)del	Likely pathogenic
1333965	NM_012452.3(TNFRSF13B):c.102C>A (p.Cys34Ter)	Likely pathogenic
2633419	NM_012452.3(TNFRSF13B):c.303_306delinsTTG (p.Tyr102fs)	Likely pathogenic

SpliceAI

858 predictions. Top by Δscore:

Variant	Effect	Δscore
17:16972013:A:AC	donor_gain	1.0000
17:16972014:C:CC	donor_gain	1.0000
17:16972014:CAG:C	donor_gain	1.0000
17:16972014:CAGCG:C	donor_gain	1.0000
17:16948979:TGACC:T	acceptor_gain	0.9900
17:16948982:CC:C	acceptor_gain	0.9900
17:16948983:CC:C	acceptor_gain	0.9900
17:16948984:C:T	acceptor_gain	0.9900
17:16952444:A:AC	donor_gain	0.9900
17:16952445:C:CC	donor_gain	0.9900
17:16972009:ACT:A	donor_loss	0.9900
17:16972010:CTC:C	donor_loss	0.9900
17:16972011:TCA:T	donor_loss	0.9900
17:16972012:CA:C	donor_loss	0.9900
17:16972013:ACA:A	donor_loss	0.9900
17:16972014:CA:C	donor_gain	0.9900
17:16948984:C:CC	acceptor_gain	0.9800
17:16948985:T:C	acceptor_loss	0.9800
17:16969925:A:AC	donor_gain	0.9800
17:16972009:A:AC	donor_gain	0.9800
17:16972010:C:CC	donor_gain	0.9800
17:16972013:ACAG:A	donor_gain	0.9800
17:16972014:CAGC:C	donor_gain	0.9800
17:16972023:T:TA	donor_gain	0.9800
17:16963355:C:CA	donor_gain	0.9700
17:16942028:T:A	donor_gain	0.9600
17:16952445:CTG:C	donor_gain	0.9600
17:16956120:C:CC	acceptor_gain	0.9600
17:16963334:T:TA	donor_gain	0.9600
17:16948980:GACC:G	acceptor_gain	0.9500

AlphaMissense

1914 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:16940449:A:G	C170R	0.980
17:16948949:G:C	F78L	0.979
17:16948949:G:T	F78L	0.979
17:16948951:A:G	F78L	0.979
17:16939733:G:C	F232L	0.978
17:16939733:G:T	F232L	0.978
17:16939735:A:G	F232L	0.978
17:16939727:G:C	F234L	0.976
17:16939727:G:T	F234L	0.976
17:16939729:A:G	F234L	0.976
17:16948884:C:G	C100S	0.976
17:16948885:A:T	C100S	0.976
17:16940462:G:C	S165R	0.971
17:16940462:G:T	S165R	0.971
17:16940464:T:G	S165R	0.971
17:16948917:C:G	C89S	0.971
17:16948918:A:T	C89S	0.971
17:16948917:C:T	C89Y	0.969
17:16948872:C:G	C104S	0.968
17:16948873:A:T	C104S	0.968
17:16948918:A:G	C89R	0.968
17:16948944:T:G	D80A	0.967
17:16948872:C:T	C104Y	0.965
17:16948944:T:A	D80V	0.965
17:16940455:C:G	G168R	0.964
17:16940455:C:T	G168R	0.964
17:16948905:C:G	C93S	0.962
17:16948906:A:T	C93S	0.962
17:16948944:T:C	D80G	0.962
17:16952525:C:A	W40C	0.961

dbSNP variants (sampled 300 via entrez): RS1000091022 (17:16952580 G>A), RS1000245404 (17:16947258 A>G), RS1000259676 (17:16958424 T>A,C), RS1000282636 (17:16964245 A>G), RS1000299432 (17:16947661 C>G,T), RS1000458954 (17:16942531 C>T), RS1000546122 (17:16952792 T>A), RS1000594108 (17:16948321 T>C), RS1000751759 (17:16953490 C>T), RS1000810170 (17:16942323 G>A), RS1000850165 (17:16938691 C>G), RS1000858807 (17:16960044 G>A), RS1001002883 (17:16969780 CT>C), RS1001013016 (17:16965190 T>C), RS1001048055 (17:16948055 T>C)

Disease associations

OMIM: gene MIM:604907 | disease phenotypes: MIM:240500, MIM:609529, MIM:607594, MIM:605258, MIM:615577, MIM:146830, MIM:137100

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency, common variable, 2	Strong	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, 2	Definitive	AR

Mondo (8): immunodeficiency, common variable, 2 (MONDO:0009413), immunoglobulin A deficiency 2 (MONDO:0012291), common variable immunodeficiency (MONDO:0015517), immunodeficiency, common variable, 1 (MONDO:0011864), hyper-IgM syndrome type 2 (MONDO:0011528), immunodeficiency, common variable, 10 (MONDO:0014260), immune deficiency, familial variable (MONDO:0007814), IgAD1 (MONDO:0007644)

Orphanet (3): OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Late-onset combined immunodeficiency due to ICOS deficiency (Orphanet:695183), Hyper-IgM syndrome type 2 (Orphanet:101089)

HPO phenotypes

28 total (28 of 28 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:0004315	Decreased circulating IgG concentration
HP:0004332	Abnormal lymphocyte morphology
HP:0004798	Recurrent infection of the gastrointestinal tract
HP:0005387	Combined immunodeficiency
HP:0005425	Recurrent sinopulmonary infections
HP:0006532	Recurrent pneumonia
HP:0011108	Recurrent sinusitis
HP:0011839	Abnormal total T cell count
HP:0011840	Abnormal T cell physiology
HP:0410301	Partial absence of specific antibody response to unconjugated pneumococcus vaccine

GWAS associations

54 associations (top):

Study	Trait	p-value
GCST000583_9	Hematological and biochemical traits	3.000000e-10
GCST001017_7	Diabetic retinopathy	7.000000e-06
GCST001496_1	Non-albumin protein levels	1.000000e-14
GCST001496_3	Non-albumin protein levels	7.000000e-24
GCST001600_1	IgG levels	1.000000e-12
GCST001698_2	Serum total protein levels	1.000000e-09
GCST001698_5	Serum total protein levels	2.000000e-11
GCST001698_6	Serum total protein levels	2.000000e-18
GCST001813_5	Hematology traits	8.000000e-24
GCST002140_5	Multiple myeloma	8.000000e-09
GCST002921_7	Multiple myeloma	6.000000e-11
GCST002922_8	Multiple myeloma and monoclonal gammopathy	3.000000e-10
GCST003995_3	Tonsillectomy	3.000000e-21
GCST004028_9	Immunoglobulin light chain (AL) amyloidosis	2.000000e-06
GCST004603_174	Platelet count	2.000000e-11
GCST004607_71	Plateletcrit	6.000000e-11
GCST004607_72	Plateletcrit	1.000000e-19
GCST004608_219	Granulocyte percentage of myeloid white cells	3.000000e-15
GCST004609_77	Monocyte percentage of white cells	1.000000e-14
GCST004625_237	Monocyte count	8.000000e-12
GCST004625_238	Monocyte count	3.000000e-27
GCST004627_168	Lymphocyte count	2.000000e-10
GCST005014_25	Tonsillectomy	3.000000e-21
GCST005987_10	Albumin-globulin ratio	5.000000e-166
GCST005988_13	Serum albumin levels	2.000000e-11
GCST005989_34	Serum total protein levels	3.000000e-107
GCST005990_21	Non-albumin protein levels	1.000000e-193
GCST006000_4	Immunoglobulin measurement (zinc sulfate turbidity test)	1.000000e-26
GCST006032_13	Sodium levels	8.000000e-10
GCST007824_10	Monoclonal gammopathy of undetermined significance	9.000000e-07

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:0004536	total blood protein measurement
EFO:0005128	albumin:globulin ratio measurement
EFO:0007924	tonsillectomy risk measurement
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004587	lymphocyte count
EFO:0009282	sodium measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007874	gut microbiome measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004527	mean corpuscular hemoglobin
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004305	erythrocyte count
EFO:0007986	reticulocyte count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330
C564136	Immune Deficiency, Familial Variable (supp.)
C536290	Immunoglobulin a deficiency 1 (supp.)
C536291	Immunoglobulin a deficiency 2 (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

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
bisphenol S	affects cotreatment, increases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Biological Factors	increases expression	1
Demecolcine	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Zinc	increases expression	1
Aflatoxin B1	increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KU30	Jurkat KZ142 clone #24	Cancer 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)