Submissions for variant NM_012452.3(TNFRSF13B):c.61+5G>A

gnomAD frequency: 0.00005  dbSNP: rs374249932

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055363	SCV001219751	uncertain significance	Immunodeficiency, common variable, 2	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the TNFRSF13B gene. It does not directly change the encoded amino acid sequence of the TNFRSF13B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374249932, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TNFRSF13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 851047). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV002469333	SCV002765411	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001055363	SCV005685319	uncertain significance	Immunodeficiency, common variable, 2	2024-06-10	criteria provided, single submitter	clinical testing	The TNFRSF13B c.61+5G>A variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by two submitters. This variant is only observed on 5/251,314 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on TNFRSF13B function. Additionally, other variants at this splice donor (c.61+2T>C, c.61+2T>A, c.61+1G>A, c.61+1G>T) are classified as pathogenic or likely pathogenic in ClinVar. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.