rs876657634

Positions:

• chr10-119672477-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004281.4(BAG3):​c.730C>T​(p.Gln244Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAG3 NM_004281.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.17

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-119672477-C-T is Pathogenic according to our data. Variant chr10-119672477-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228246.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.730C>T	p.Gln244Ter	stop_gained	3/4	ENST00000369085.8
BAG3	XM_005270287.2	c.730C>T	p.Gln244Ter	stop_gained	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.730C>T	p.Gln244Ter	stop_gained	3/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1	c.556C>T	p.Gln186Ter	stop_gained	4/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change creates a premature translational stop signal (p.Gln244*) in the BAG3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). 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: 228246). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2017

The p.Gln244X variant in BAG3 has been identified by our laboratory in 1 individ ual with DCM and segregated with disease in 2 affected relatives (including 1 ob ligate carrier; LMM data). It was also absent from large population studies. Thi s variant has been reported in ClinVar (Variation ID 228246). This nonsense vari ant leads to a premature termination codon at position 244, which is predicted t o lead to a truncated or absent protein. Nonsense and other truncating variants in BAG3 are associated with DCM (Norton 2011, Villard 2011, Konersman 2015). In summary, although additional studies are required to fully establish its clinica l significance, the p.Gln244X variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		6.0

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: rs876657634; hg19: chr10-121431989;