17-16948947-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5
The NM_012452.3(TNFRSF13B):c.236A>G(p.Tyr79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,188 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 0 hom. )
Consequence
TNFRSF13B
NM_012452.3 missense
NM_012452.3 missense
Scores
7
4
4
Clinical Significance
Conservation
PhyloP100: 3.58
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.
PM1
?
In a repeat TNFR-Cys 2 (size 34) in uniprot entity TR13B_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_012452.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.803
PP5
?
Variant 17-16948947-T-C is Pathogenic according to our data. Variant chr17-16948947-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281110.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=4}. Variant chr17-16948947-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF13B | NM_012452.3 | c.236A>G | p.Tyr79Cys | missense_variant | 3/5 | ENST00000261652.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF13B | ENST00000261652.7 | c.236A>G | p.Tyr79Cys | missense_variant | 3/5 | 1 | NM_012452.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000175 AC: 44AN: 251394Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135866
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GnomAD4 exome AF: 0.000278 AC: 406AN: 1461890Hom.: 0 Cov.: 35 AF XY: 0.000268 AC XY: 195AN XY: 727246
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2023 | Identified in the presence of a second TNFRSF13B variant in siblings with IgG subclass deficiency, one of whom had recurrent infections requiring IVIG therapy; however, their heterozygous mother was unaffected and father with dysgammaglobulinemia or IgG subclass deficiency was not tested (Salzer et al., 2009); Identified heterozygous in a patient with a personal history suggestive of common variable immune deficiency in published literature, though clinical details and segregation information were not provided (Hou et al., 2020); Identified heterozygous in a patient with recurrent pneumonia, recurrent gastroenteritis, and chronic oral herpes lesions in published literature, though segregation information was not provided (Engelbrecht et al., 2021); Surface expression studies support that the Y79C variant is damaging to the TNFRSF13B protein (Fried et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18954329, 21458042, 22884984, 18981294, 32581362, 21419480, 34093558, 31980526) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 26, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 19, 2015 | - - |
not specified Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 07, 2017 | - - |
Immunodeficiency, common variable, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the TNFRSF13B protein (p.Tyr79Cys). This variant is present in population databases (rs72553876, gnomAD 0.05%). This missense change has been observed in individual(s) with common variable immunodeficiency (CVID), IgG subclass deficiency, and/or primary immune disorders (PMID: 18981294, 22884984, 32581362, 34093558). ClinVar contains an entry for this variant (Variation ID: 281110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNFRSF13B protein function. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 18954329, 21419480, 21458042). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 01, 2021 | ACMG classification criteria: PS3 supporting, PM3 supporting, PP3 - |
TNFRSF13B-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 02, 2023 | The TNFRSF13B c.236A>G variant is predicted to result in the amino acid substitution p.Tyr79Cys. This variant has been reported in the compound heterozygous state in two individuals with IgG subclass deficiency from the same family (Salzer et al. 2009. PubMed ID: 18981294). Of note, this variant was also seen in the heterozygous state in a healthy member of that same family (Salzer et al. 2009. PubMed ID: 18981294). Functional analysis showed that the c.236A>G variant leads to a reduction in protein activity as compared to wild-type (Fried et al. 2011. PubMed ID: 21419480). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
DEOGEN2
Pathogenic
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;D
Vest4
MVP
MPC
0.084
ClinPred
T
GERP RS
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gMVP
Splicing
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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