TNFRSF13B

protein-coding

TNF receptor superfamily member 13B, the group of CD molecules|Tumor necrosis factor receptor superfamily

Gene summary

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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012452.3

Inheritance

AR, AD

ClinVar variants

P:52U:193B:98

Top phenotype

Immunoglobulin A deficiency 2; Common variable immunodeficiency 2

gnomAD constraint

pLI —, LoF o/e 1.73

Max pathogenic AF

—

Genomic locus

chr17:16,929,816-16,972,118

External References & Databases

Ensembl (ENSG00000240505)

Transcript & Mutation Effects

hg38 • Region Span ~42.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency, common variable, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009413

Submitter: Ambry Genetics

immunodeficiency, common variable, 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009413

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency, common variable, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009413

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency, common variable, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009413

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

immunodeficiency, common variable, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009413

Submitter: ClinGen

TNFRSF13B was first reported in relation to autosomal recessive common variable immunodeficiency 2 (CVID 2) in 2001 (Salzer U, et al., 2005, PMID: 16007087 and Castigli E, et al., 2005, PMID: 16007086). TNFRSF13B encodes TACI (transmembrane activator and CAML interactor), a transmembrane protein of the TNF receptor superfamily found predominantly on the surface of B cells. TACI is a receptor on B cells for APRIL, BAFF, syndecan-2, besides interacting with CAML. TACI mediates activation of transcription factors NF-AT, NF-kappa-B, and AP-1, and is involved in the stimulation of B- and T-cell function and the regulation of humoral immunity. CVID is a clinically and genetically heterogeneous entity, primarily presenting as an antibody deficiency with low levels of serum IgG, IgA, and/or IgM, functional antibody deficiency, and recurrent sinopulmonary bacterial infections. In addition, non-infectious complications linked to underlying immune dysregulation are present in a subset of patients. Evidence supporting the TNFRSF13B gene-disease relationship includes case-level data and experimental data. At least 14 unique variants have been reported in humans with biallelic variants, including nonsense, frameshift, splicing, and missense. Biallelic variants in this gene have been reported in at least 12 probands in 7 publications (PMIDs: 16007086, 19779048, 19629655, 27123465, 16007087, 18981294, 17983875), and segregated with disease in four additional family members. Experimentally, this gene-disease relationship is supported by its expression in B cells (PMID: 15240667), its role in class switch recombination (PMID: 15630136), which is altered in patient cells (PMID: 16007087), and two mouse models (PMIDs: 11429549, 11371359) which recapitulate features of CVID. In summary TNFRSF13B is definitively associated with autosomal recessive CVID 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, variants in TNFRSF13B have been observed in CVID patients in both the monoallelic and biallelic forms. Heterozygous mutations in TNFRSF13B may lead to impaired ligand binding and contribute to defects in cell activation and B cell tolerance, but the connection between heterozygous mutations and disease is not clear, because normal relatives may have the same mutations without evidence of immune deficiency. Since additional genetic or environmental factors are required to induce immune deficiency, only biallelic cases are considered here for the relationship between TNFRSF13B and CVID 2. On the other hand, heterozygous TACI variants do affect B cell activation and peripheral tolerance resulting in autoimmunity (Romberg et al., 2013; PMID: 24051380), likely due to a dominant negative effect (Romberg et al., 2015; PMID: 26100089). Whereas, patients with Smith-Magenis syndrome (with a deletion on 17p) have haploinsufficiency of TACI but do not develop autoimmunity or abnormal B cell function. Additionally, epistatic interactions have been reported between TNFRSF13B and other genes, such as TCF3 with similar function, resulting in a digenic cause of humoral immunodeficiency (Ameratunga et al., 217; PMID: 29114388).

immunodeficiency, common variable, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009413

Submitter: G2P

Clinical Genomic Database (CGD)

Immunoglobulin A deficiency 2; Common variable immunodeficiency 2AD/AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: In CVID2, prophylaxis and early and aggressive treatment of infections may be beneficial; In most cases, IGA deficiency 2 is not associated with any illness, though some may have increased infections and autoimmune disorders (other sequelae have been reported, but the molecular causes in these patients are unclear)

Refs: 11720003; 16007086; 16049503; 16007087; 18981294; 19629655; 20156508; 22076597; 22627058

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNFRSF13B variants in ClinVar

15 Conditions Cataloged

Immunodeficiency, common variable, 2Total: 334

not providedTotal: 93

not specifiedTotal: 53

Inborn genetic diseasesTotal: 44

TNFRSF13B-related disorderTotal: 41

Immunoglobulin A deficiency 2Total: 35

Common variable immunodeficiencyTotal: 5

Immunodeficiency, common variable, 1Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012452.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	79 clinvar		83
missense	3 clinvar	3 clinvar	176 clinvar	19 clinvar		201
nonsense	7 clinvar	9 clinvar	3 clinvar			19
start loss			1 clinvar			1
frameshift	6 clinvar	17 clinvar	8 clinvar			31
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	1 clinvar			8
Total	19	33	193	98	0	343

Highest pathogenic variant AF is 0.005440998

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012452.3	RefSeq	NP_036584.1	5	MANE Select
ENST00000261652.7	Ensembl	ENSP00000261652.2	5	MANE Select
ENST00000579315.5	Ensembl	ENSP00000464069.1	4	Standard
ENST00000583789.1	Ensembl	ENSP00000462952.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary immunodeficiency - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)
Intestinal immune network for IgA production - Homo sapiens (human)
yaci and bcma stimulation of b cell immune responses
TNFR2 non-canonical NF-kB pathway

Biological Process

B cell homeostasis
hematopoietic progenitor cell differentiation
adaptive immune response
cell surface receptor signaling pathway
negative regulation of B cell proliferation

Molecular Function

protein binding
signaling receptor activity

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261652
Coding exons: 5
Length: 42584
Individuals with no LoFs: 125547
Homozygous LoFs: 0
Heterozygous LoFs: 201
Defined: 125748
p: 0.000800

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.20	215	171	1.26	0.0000103	1895
Missense (PolyPhen)		69	41.182	1.6755		566
Synonymous	-0.988	82	71.4	1.15	0.00000443	589
Loss of Function	-2.17	18	10.4	1.73	5.35e-7	123

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00069	0.00069	rare
Ashkenazi Jewish	0.0051	0.0051	notable
East Asian	0.0011	0.0011	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00077	0.00076	rare
South Asian	0.00029	0.00029	rare
Other	0.00081	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. {ECO:0000269|PubMed:10956646, ECO:0000269|PubMed:10973284}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:16007086}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.245

Intolerance Scores

LoFtool: 0.218
RVIS EVS: 0.53
RVIS percentile EVS: 80.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.953

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium