Primary immunodeficiency or monogenic inflammatory bowel disease
Gene: TNFRSF13B
Additional expert review from Zornitza Stark. Have discussed with the Genomics England Clinical Team and we have decided to keep this gene Red on this panel until more evidence is available.Created: 18 May 2020, 9:14 a.m. | Last Modified: 18 May 2020, 9:14 a.m.
Panel Version: 2.169
2018: Agree this gene is difficult to categorise. We have decided to include the gene in our panels, but report only the specific variants for which there is published evidence, and to report them as contributory rather than solely causative.
2020: Variants in this gene do not readily fit the monogenic rare disease paradigm, but nevertheless there is evidence they make a contribution to CVID pathogenesis. We have 'whitelisted' specific variants and are reporting them separately as susceptibility alleles. It is unlikely that further evidence will alter this interpretation, this is more of a question about reporting policy.Created: 15 Jul 2018, 3:32 p.m. | Last Modified: 12 Apr 2020, 1:58 a.m.
Panel Version: 2.51
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Rated red following advice from the Genomics England clinical team. Further information is needed about this gene and its interactions.Created: 5 Jul 2018, 8:59 p.m.
Comment on publications: Added publications relating to incomplete penetrance, gain of function and epistatic interactions with TCF3Created: 3 Jul 2018, 12:26 p.m.
Consulting with the Genomics England Clinical team as to the appropriate colour rating of this gene.Created: 3 Jul 2018, 12:22 p.m.
Although associated with Immunodeficiency, common variable, 2 and Immunoglobulin A deficiency 2 in OMIM and with Immunodeficiency, common variable, 2 in Gene2Phenotype and 6 variants reported in OMIM, there is some suggestion that variants in TNFRSF13B may not be solely causative. For example a study by Salzer et al 2009 (PMID:18981294) report on 7 familial cases of CVID where variants in TNFRSF13B were found, but also note that there are healthy or only mildly affected family members who have monoallelic or biallelic mutations, therefore mutations in TNFRSF13B are not 100% penetrant, and that two of the CVID patients have 2 wild-type TNFRSF13B alleles, hence mutations in TNFRSF13B/TACI are a contributing factor to develop CVID but are not solely causative.
A gain of function variant has also been reported by Peng et al 2017 (PMID: 28834165) in a family with two children with immune thrombocytopenia and a heterozygous G76S variant in TNFRSF13B. The healthy father was also heterozygous for this variant indicating incomplete penetrance.
Ameratunga et al 2017 (PMID: 29114388) report a family with a proband heterozygous for variants in both TNFRSF13B (C104R) and TCF3 (T168fsX191) and a severe CVID-like disorder while a sibling homozygous for the TNFRSF13B (C104R) only is in good health despite profound hypogammaglobulinemia and mild cytopenias and a son heterozygous for the TCF3 variant only has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency. Thus it appears that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder.Created: 3 Jul 2018, 12:09 p.m.
Additional external review this gene was reviewed again. Decided to keep Red on this panel, variants in this gene are contributory and not solely causative, more evidence is needed to understand the contribution to the disorder. We currently do not report contributory variants of a disorder, only causative.Created: 21 Sep 2018, 10:15 a.m.
OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TNFRSF13B (TACI) .PanelApp HGNC gene symbol check: TNFRSF13B . IUIS Disease: TACI deficiency . IUIS Inheritance: AD or AR .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Variable clinical expression. IUIS Major category: Predominantly Antibody Deficiencies. IUIS Subcategory: Severe Reduction in at Least 2 Serum Immunoglobulin Isotypes with Normal or Low Number of B Cells, CVID PhenotypeCreated: 2 Jul 2018, 10:35 a.m.
This gene was present in the original PanelApp PID panel dataset (review in April 2018) rated as Amber. The gene is present in the external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.Created: 20 Apr 2018, 10:27 a.m.
Original metadata downloaded from ESID Registry. ESID_Gene_original: TACI, PanelApp HGNC gene symbol check: TNFRSF13B, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Predominantly antibody disorders / Hypogammaglobulinemias / Common variable immunodeficiency disorders (CVID); Predominantly antibody disorders / Hypogammaglobulinemias / IgA with IgG subclass deficiency; Predominantly antibody disorders / Hypogammaglobulinemias / Isolated IgG subclass deficiency; Predominantly antibody disorders / Hypogammaglobulinemias / Selective IgA deficiencyCreated: 17 Apr 2018, 12:29 p.m.
Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TNFRSF13B, GRID_Gene_Symbol: TNFRSF13B, GRID_Transcript_ENS_Community submitted: ENST00000261652, GRID_Transcript_RefSeq: NM_012452.2, GRID_Transcript_ENS_used_on_Production: ENST00000261652Created: 17 Apr 2018, 12:12 p.m.
Comment when marking as ready: Three negative expert reviews, 6 LOF variants reported in two publications. Association with Immunodeficiency, common variable, 2, 240500 in Gen2PhenCreated: 11 May 2016, 10:35 a.m.
Variants seem to behave as risk alleles and do not appear to act alone when disease occursCreated: 19 Oct 2015, 2:37 p.m.
Mode of inheritance
Other
Phenotypes
CVID; IGAD
Source IUIS Classification December 2019 was added to TNFRSF13B. Added phenotypes Variable clinical expression; Predominantly Antibody Deficiencies for gene: TNFRSF13B Publications for gene TNFRSF13B were updated from 16007086; 16007087; 18981294; 28834165; 29114388 to 16007086; 18981294; 29114388; 16007087; 32048120; 28834165; 32086639
2018-07-12 Louise Daugherty (Genomics England Curator) promoted panel to v1.0. Reviews were assessed, and panel was revised according to expert reviews and further in-house curation based on PanelApp guidelines. Previous panels (A- or hypo-gammaglobulinaemia, Congenital neutropaenia, Agranulocytosis, Combined B and T cell defect, Inherited complement deficiency and SCID panels) that were merged with this panel, were checked again for any changes/new reviews prior to versioning of this panel, these merged panels are now retired/made internal.
Gene: tnfrsf13b has been classified as Red List (Low Evidence).
Publications for gene: TNFRSF13B were set to 16007086; 16007087; 18981294; 28834165; 29114388
Phenotypes for gene TNFRSF13B were set to Immunodeficiency, common variable, 2, Immunoglobulin A deficiency 2, 609529, Immunodeficiency, common variable, 2, 240500, Common variable immunodeficiency disorders (CVID), Selective IgA deficiency, IgA with IgG subclass deficiency, Isolated IgG subclass deficiency, CVID, IGAD, Variable clinical expression, Predominantly Antibody Deficiencies
IUIS Classification February 2018 was added to TNFRSF13B. Panel: Primary immunodeficiency disorders
Victorian Clinical Genetics Services was added to TNFRSF13B. Panel: Primary immunodeficiency disorders
Phenotypes for TNFRSF13B were set to Immunodeficiency, common variable, 2; Immunoglobulin A deficiency 2, 609529; Immunodeficiency, common variable, 2, 240500; Common variable immunodeficiency disorders (CVID); Selective IgA deficiency; IgA with IgG subclass deficiency; Isolated IgG subclass deficiency; CVID; IGAD
ESID Registry 20171117 was added to TNFRSF13B. Panel: Primary immunodeficiency disorders Phenotypes for gene TNFRSF13B were set to Immunodeficiency, common variable, 2, Immunoglobulin A deficiency 2, 609529, Immunodeficiency, common variable, 2, 240500, Common variable immunodeficiency disorders (CVID), Selective IgA deficiency, IgA with IgG subclass deficiency, Isolated IgG subclass deficiency
Phenotypes for gene TNFRSF13B were set to Immunodeficiency, common variable, 2, Immunoglobulin A deficiency 2, 609529, Immunodeficiency, common variable, 2, 240500
GRID V2.0 was added to TNFRSF13B. Panel: Primary immunodeficiency disorders Phenotypes for gene TNFRSF13B were set to Immunodeficiency, common variable, 2, Immunoglobulin A deficiency 2, 609529, Immunodeficiency, common variable, 2, 240500
TNFRSF13B Source: GOSH PID 20171203 was removed from gene: TNFRSF13B
GOSH PID v.8.0 was added to TNFRSF13B. Panel: Primary immunodeficiency disorders
GOSH PID 20171203 was added to TNFRSF13B. Panel: Primary immunodeficiency disorders
TNFRSF13B was added to Primary immunodeficiency disorders panel. Sources: Expert Review Amber, A- or hypo-gammaglobulinaemia v1.25
TNFRSF13B was created by Louise Daugherty