rs201021960
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Strong
The NM_012452.3(TNFRSF13B):c.706G>T(p.Glu236Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000722 in 1,605,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000069 ( 0 hom. )
Consequence
TNFRSF13B
NM_012452.3 stop_gained
NM_012452.3 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.98
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 Uncertain_significance. Variant got 4 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.2 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF13B | NM_012452.3 | c.706G>T | p.Glu236Ter | stop_gained | 5/5 | ENST00000261652.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF13B | ENST00000261652.7 | c.706G>T | p.Glu236Ter | stop_gained | 5/5 | 1 | NM_012452.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000143 AC: 35AN: 244442Hom.: 0 AF XY: 0.000189 AC XY: 25AN XY: 132396
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GnomAD4 exome AF: 0.0000695 AC: 101AN: 1453588Hom.: 0 Cov.: 35 AF XY: 0.0000707 AC XY: 51AN XY: 721840
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GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 27, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2023 | Identified in the heterozygous state and with a second variant in TNFRSF13B in patients with common variable immune deficiency (Pulvirenti et al., 2016; Rojas-Restrepo et al., 2021); Nonsense variant predicted to result in protein truncation, as the last 58 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD.; This variant is associated with the following publications: (PMID: 26284228, 25205549, 36155879, 31150062, 27123465, 34441032, 34975878) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2020 | - - |
Immunodeficiency, common variable, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2022 | This sequence change creates a premature translational stop signal (p.Glu236*) in the TNFRSF13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the TNFRSF13B protein. This variant is present in population databases (rs201021960, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with antibody deficiency and/or common variable immune deficiency (CVID) and pancreatic cancer (PMID: 27123465, 34975878). ClinVar contains an entry for this variant (Variation ID: 538709). Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on TNFRSF13B gene expression (PMID: 25205549). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Immunoglobulin A deficiency 2;C3150354:Immunodeficiency, common variable, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 14, 2022 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
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Uncertain
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Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;D;D;D
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at