rs139232658
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004281.4(BAG3):c.181-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,613,874 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_004281.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00294 AC: 448AN: 152196Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000757 AC: 190AN: 250886Hom.: 0 AF XY: 0.000575 AC XY: 78AN XY: 135678
GnomAD4 exome AF: 0.000367 AC: 536AN: 1461560Hom.: 1 Cov.: 32 AF XY: 0.000320 AC XY: 233AN XY: 727112
GnomAD4 genome AF: 0.00294 AC: 448AN: 152314Hom.: 1 Cov.: 33 AF XY: 0.00316 AC XY: 235AN XY: 74466
ClinVar
Submissions by phenotype
not specified Benign:8
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c.181-9T>A in Intron 01 of BAG3: This variant is not expected to have clinical s ignificance because it has been identified in 1.0% (38/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs139232658). -
Variant summary: BAG3 c.181-9T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00076 in 250886 control chromosomes, predominantly at a frequency of 0.0093 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 238 fold of the estimated maximal expected allele frequency for a pathogenic variant in BAG3 causing Dilated Cardiomyopathy phenotype (3.9e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.181-9T>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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not provided Benign:2
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Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at