chr22-41925447-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_052945.4(TNFRSF13C):c.475C>T(p.His159Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00584 in 1,612,458 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_052945.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00581 AC: 884AN: 152158Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00571 AC: 1423AN: 249214Hom.: 10 AF XY: 0.00583 AC XY: 788AN XY: 135116
GnomAD4 exome AF: 0.00584 AC: 8528AN: 1460182Hom.: 45 Cov.: 31 AF XY: 0.00605 AC XY: 4394AN XY: 726368
GnomAD4 genome AF: 0.00581 AC: 884AN: 152276Hom.: 3 Cov.: 32 AF XY: 0.00540 AC XY: 402AN XY: 74458
ClinVar
Submissions by phenotype
Immunodeficiency, common variable, 4 Uncertain:1Benign:2
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The TNFRSF13C c.475C>T; p.His159Tyr variant (rs61756766) is reported in the literature in multiple individuals affected with various autoimmune diseases, including common variable immunodeficiency (CVID), non-Hodgkin lymphoma, and Sjogren syndrome (Abolhassani 2019, Hildebrand 2010, Kutukculer 2012, Losi 2005, Lougaris 2014, Papageorgiou 2015), but also in healthy controls (Losi 2005, Papageorgiou 2015). Additionally, several of the affected individuals also carried the p.Pro21Arg variant (Kutukculer 2012, Lougaris 2014), including one CVID family in which these two variants were confirmed to be on the same chromosome (Lougaris 2016). This variant is reported in ClinVar (Variation ID: 440345), and is found in the general population with an overall allele frequency of 0.56% (1575/280578 alleles, including 10 homozygotes) in the Genome Aggregation Database. The histidine at codon 159 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show an increase in immunoglobulin production compared to wild-type cells in vitro (Hildebrand 2010), and a reduced amount of protein on patient cells in combination with the p.Pro21Arg variant (Lougaris 2016). Due to conflicting information and the lack of information regarding the association with the p.Pro21Arg variant, the clinical significance of the p.His159Tyr variant alone or in combination with p.Pro21Arg in CVID remains uncertain. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided Benign:1
TNFRSF13C: BS2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at