rs727505109
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_004281.4(BAG3):c.1067delC(p.Pro356HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_004281.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BAG3 | ENST00000369085.8 | c.1067delC | p.Pro356HisfsTer7 | frameshift_variant | Exon 4 of 4 | 1 | NM_004281.4 | ENSP00000358081.4 | ||
BAG3 | ENST00000450186.1 | c.890delC | p.Pro297HisfsTer7 | frameshift_variant | Exon 5 of 5 | 5 | ENSP00000410036.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 77
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Pathogenic:1
This sequence change creates a premature translational stop signal (p.Pro356Hisfs*7) in the BAG3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 220 amino acid(s) of the BAG3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. ClinVar contains an entry for this variant (Variation ID: 179764). This variant disrupts a region of the BAG3 protein in which other variant(s) (p.Lys449*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Primary dilated cardiomyopathy Pathogenic:1
The p.Pro356fs variant in BAG3 has been identified by our laboratory in 1 Caucas ian individual with DCM. It was absent from large population studies. This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 356 and leads to a premature termination codon 7 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of functions variants in BAG3 have been reported to be dis ease-causing (Norton 2011, Villard, 2011). In summary, although additional studi es are required to fully establish its clinical significance, the p.Pro356fs var iant is likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at