rs72553875
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_012452.3(TNFRSF13B):c.204dupA(p.Leu69fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00035 ( 1 hom. )
Consequence
TNFRSF13B
NM_012452.3 frameshift
NM_012452.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.25
Genes affected
TNFRSF13B (HGNC:18153): (TNF receptor superfamily member 13B) 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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-16948978-G-GT is Pathogenic according to our data. Variant chr17-16948978-G-GT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 322029.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=8, Likely_pathogenic=2}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TNFRSF13B | NM_012452.3 | c.204dupA | p.Leu69fs | frameshift_variant | 3/5 | ENST00000261652.7 | NP_036584.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TNFRSF13B | ENST00000261652.7 | c.204dupA | p.Leu69fs | frameshift_variant | 3/5 | 1 | NM_012452.3 | ENSP00000261652.2 |
Frequencies
GnomAD3 genomes 0.000309 AC: 47AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000406 AC: 102AN: 251000Hom.: 0 AF XY: 0.000413 AC XY: 56AN XY: 135650
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GnomAD4 exome AF: 0.000350 AC: 511AN: 1461832Hom.: 1 Cov.: 35 AF XY: 0.000348 AC XY: 253AN XY: 727212
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GnomAD4 genome 0.000309 AC: 47AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74434
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:13Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Immunodeficiency, common variable, 2 Pathogenic:5
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Leu69Thrfs*12) in the TNFRSF13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNFRSF13B are known to be pathogenic (PMID: 16007087, 27123465). This variant is present in population databases (rs72553875, gnomAD 0.6%). This premature translational stop signal has been observed in individuals with common variable immunodeficiency or IgA deficiency (PMID: 16007086, 17392798, 18981294, 22884984, 26046366, 26100089, 27123465). ClinVar contains an entry for this variant (Variation ID: 322029). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 26, 2023 | PVS1, PS3 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.040%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000322029 / PMID: 16007086). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 16, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 26, 2024 | Reported in association with both autosomal dominant and autosomal recessive forms of CVID and immunoglobulin A deficiency; however, most commonly associated with autosomal recessive inheritance (PMID: 16007086, 18981294, 21547394, 27123465); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26100089, 27266541, 26046366, 23956760, 18981294, 22884984, 21547394, 30090215, 16007086, 27123465) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Immunodeficiency, common variable, 1 Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" | May 01, 2022 | - - |
Hyper-IgM syndrome type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Aug 06, 2023 | - - |
TNFRSF13B-related disorder Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 06, 2023 | The TNFRSF13B c.204dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu69Thrfs*12). This variant has been reported in either the heterozygous or compound heterozygous state in several individuals with either common variable immunodeficiency (CVID) or IgA deficiency (IgAD) (Castigli et al. 2005. PubMed ID: 16007086; Salzer et al. 2009. PubMed ID: 18981294; Speletas et al. 2011. PubMed ID: 21547394; Pulvirenti et al. 2016. PubMed ID: 27123465). At least one patient with this variant developed non-Hodgkin lymphoma as well as CVID (Pulvirenti et al. 2016. PubMed ID: 27123465). This variant is reported in 0.56% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-16852292-G-GT). Frameshift variants in TNFRSF13B are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 08, 2021 | TNFRSF13B NM_012452.2 exon 3 p.Leu69Thrfs*12 (c.204dupA):This variant has been reported in the literature in at least 5 individuals with Common Variable Immunodeficiency (CVID) or IgA deficiency (IgAD), segregating with disease in at least 4 affected family members. This variant has also been identified in 1 individual with tonsillar hypertrophy (Castigli 2005 PMID:16007086, Castigli 2007 PMID:17392798, Salzer 2009 PMID:18981294, Speletas 2011 PMID:21547394, Freiberger 2012 PMID:22884984, Speletas 2013 PMID:23956760, Pulvirenti 2016 PMID:27123465). This variant is present in 0.5% (58/10358) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16852292-G-GT?dataset=gnomad_r2_1). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID: 322029). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant suggesting no impact to protein expression, activation responses or central B-cell tolerance in naive B cells, but decreased expression on memory B cells with subsequent impaired activation and antibody secretion (Romberg 2015 PMID:26100089). This variant is a duplication of 1 nucleotide at position 204 and creates a premature stop codon 12 amino acids downstream from this location resulting in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Romberg 2015 PMID:26100089). In summary, this variant is classified as pathogenic. - |
Immunoglobulin A deficiency 2 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2005 | - - |
Common Variable Immune Deficiency, Dominant Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.204dupA (p.Leu69ThrfsTer12) variant is a frameshift variant and is predicted to result in a premature termination of the protein. The p.Leu69ThrfsTer12 variant has been reported in at least five studies in individuals with either CVID or IgA deficiency (Castigli et al. 2005; Salzer et al. 2009; Speletas et al. 2011; Freiberger et al. 2012; Pulvirenti et al. 2016) and found in a compound heterozygous state with a missense variant in three patients with CVID and in a heterozygous state in six individuals with IgA deficiency. One multigenerational family study showed this variant segregating with disease in individuals with IgA deficiency or CVID, suggesting clinical heterogeneity with a potential spectrum of disease (Castigli et al. 2005). The p.Leu69ThrfsTer12 variant was absent from at least 1250 controls, but is reported at a frequency of 0.00109 in the European American population of the Exome Sequencing Project. Functional studies show that the p.Leu69ThrfsTer12 variant results in a severely impaired secretion of IgG and IgA in B cells in response to the TACI ligand, APRIL (Castigli et al. 2005). Castigli et al. (2005) also showed there was no detectable protein product on the surface of 293 cells carrying the p.Leu69ThrfsTer12 variant. However, Salzer et al. (2009) showed a single EBV-transformed cell line carrying a heterozygous p.Leu69ThrfsTer12 variant displayed no significant differences in TACI expression or ligand binding capacity compared with controls. Based on the potential impact of frameshift variants and the supporting evidence, the p.Leu69ThrfsTer12 variant is classified as a variant of unknown significance but suspicious for pathogenicity for common variable immune deficiency. - |
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