rs1555550717
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_012452.3(TNFRSF13B):c.49del(p.Gln17ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TNFRSF13B
NM_012452.3 frameshift
NM_012452.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.34
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-16972026-TG-T is Pathogenic according to our data. Variant chr17-16972026-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 538707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF13B | NM_012452.3 | c.49del | p.Gln17ArgfsTer15 | frameshift_variant | 1/5 | ENST00000261652.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF13B | ENST00000261652.7 | c.49del | p.Gln17ArgfsTer15 | frameshift_variant | 1/5 | 1 | NM_012452.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461814Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727216
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Immunodeficiency, common variable, 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2021 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TNFRSF13B are known to be pathogenic (PMID: 16007087, 27123465). This variant has not been reported in the literature in individuals with TNFRSF13B-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln17Argfs*15) in the TNFRSF13B gene. It is expected to result in an absent or disrupted protein product. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2019 | The c.49delC variant in the TNFRSF13B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.49delC variant causes a frameshift starting with codon Glutamine 17, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Gln17ArgfsX15. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.49delC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.49delC as a likely pathogenic variant. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at