rs886039182

chr10-119676844-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004281.4(BAG3):c.1292dup(p.Val432GlyfsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BAG3 NM_004281.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.35

Genes affected

BAG3 (HGNC:939): (BAG cochaperone 3) BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-119676844-G-GA is Pathogenic according to our data. Variant chr10-119676844-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 264518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4	c.1292dup	p.Val432GlyfsTer12	frameshift_variant	4/4	ENST00000369085.8
BAG3	XM_005270287.2	c.1289dup	p.Val431GlyfsTer12	frameshift_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.1292dup	p.Val432GlyfsTer12	frameshift_variant	4/4	1	NM_004281.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 78 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2021

This sequence change creates a premature translational stop signal (p.Val432Glyfs*12) in the BAG3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acid(s) of the BAG3 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BAG3 protein in which other variant(s) (p.Glu471Argfs*95) 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. ClinVar contains an entry for this variant (Variation ID: 264518). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2020

The c.1292dupA pathogenic mutation, located in coding exon 4 of the BAG3 gene, results from a duplication of A at nucleotide position 1292, causing a translational frameshift with a predicted alternate stop codon (p.V432Gfs*12). This alteration has not been previously reported; however, loss of function alterations have been reported in numerous cases of familial dilated cardiomyopathy, including many families with strong segregation with disease (Norton N et al. Am J Hum Genet. 2011;88(3):273-82; Villard E et al. Eur Heart J. 2011;32(9):1065-76; Chami N et al. Can J Cardiol. 2014;30(12):1655-61; Feldman AM et al. J Cell Physiol. 2014;229(11):1697-702; Franaszczyk M et al. J Transl Med. 2014;12:192; van Spaendonck-Zwarts KY et al. Eur Heart J. 2014;35(32):2165-73). In addition, in Norton et al. 2011, BAG3 knockdown in a zebrafish model showed heart failure with decreased fractional shortening and pericardial effusion. This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039182; hg19: chr10-121436356;