10-119670032-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_004281.4(BAG3):c.362G>A(p.Arg121Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004281.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251444Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727242
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: BAG3 c.362G>A (p.Arg121Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.362G>A has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual within a cohort of dilated cardiomyopathy (DCM) patients (example, Horvat_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Myofibrillar Myopathy, BAG3-Related/Dilated Cardiomyopathy (DCM). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29892087). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
The p.Arg121Gln variant in BAG3 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Arg121Gln variant is uncertain. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with dilated cardiomyopathy (DCM) in published literature who harbored an additional cardiogenetic variant (PMID: 29892087); This variant is associated with the following publications: (PMID: 29892087) -
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 121 of the BAG3 protein (p.Arg121Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 29892087). ClinVar contains an entry for this variant (Variation ID: 228455). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BAG3 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. -
Cardiovascular phenotype Uncertain:1
The p.R121Q variant (also known as c.362G>A), located in coding exon 2 of the BAG3 gene, results from a G to A substitution at nucleotide position 362. The arginine at codon 121 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in a dilated cardiomyopathy (DCM) cohort (Horvat C et al. Genet Med, 2019 Jan;21:133-143). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at