rs886039044

Positions:

• chr10-119670151-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004281.4(BAG3):​c.481C>T​(p.Gln161Ter) 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q161Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAG3 NM_004281.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.07

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 12 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 10-119670151-C-T is Pathogenic according to our data. Variant chr10-119670151-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 264102.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.481C>T	p.Gln161Ter	stop_gained	2/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.481C>T	p.Gln161Ter	stop_gained	2/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.481C>T	p.Gln161Ter	stop_gained	2/4	1	NM_004281.4	ENSP00000358081	P1
BAG3	ENST00000450186.1	c.307C>T	p.Gln103Ter	stop_gained	3/5	5		ENSP00000410036

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

The p.Q161* pathogenic mutation (also known as c.481C>T), located in coding exon 2 of the BAG3 gene, results from a C to T substitution at nucleotide position 481. This changes the amino acid from a glutamine to a stop codon within coding exon 2. 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. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.81	D
MutationTaster	Benign	1.0	A
Vest4		0.90
GERP RS		5.0

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: rs886039044; hg19: chr10-121429663;