rs764125338
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_012452.3(TNFRSF13B):c.577T>C(p.Cys193Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_012452.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNFRSF13B | NM_012452.3 | c.577T>C | p.Cys193Arg | missense_variant | 4/5 | ENST00000261652.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNFRSF13B | ENST00000261652.7 | c.577T>C | p.Cys193Arg | missense_variant | 4/5 | 1 | NM_012452.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000838 AC: 21AN: 250588Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135510
GnomAD4 exome AF: 0.0000794 AC: 116AN: 1461788Hom.: 0 Cov.: 31 AF XY: 0.0000949 AC XY: 69AN XY: 727182
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74314
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2017 | The C193R variant in the TNFRSF13B gene has been reported previously in an individual with features of both autoimmune lymphoproliferative syndrome and CVID; however, this individual also harbored a variant in the CASP9 gene that may also have contributed to the phenotype (Clemente et al., 2015). Additionally, this individual harbored a nonsense variant on the same TNFRSF13B allele (in cis). The C193R variant is observed in 6/66,548 (0.009%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The C193R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret C193R as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | - - |
Immunodeficiency, common variable, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 193 of the TNFRSF13B protein (p.Cys193Arg). This variant is present in population databases (rs764125338, gnomAD 0.01%). This missense change has been observed in individual(s) with autoimmune lymphoproliferative syndrome and/or common variable immunodeficiency (PMID: 25569260, 33859323). ClinVar contains an entry for this variant (Variation ID: 449227). 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 not expected to disrupt TNFRSF13B protein function with a negative predictive value of 80%. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 18, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at