10-119651808-C-T

Position:

chr10-119651808-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_004281.4(BAG3):c.133C>T(p.Arg45Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,597,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.87

Variant links:

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]

BAG3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4 linkuse as main transcript	c.133C>T	p.Arg45Cys	missense_variant	1/4	ENST00000369085.8	NP_004272.2	O95817
BAG3	XM_005270287.2 linkuse as main transcript	c.133C>T	p.Arg45Cys	missense_variant	1/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 linkuse as main transcript	c.133C>T	p.Arg45Cys	missense_variant	1/4	1	NM_004281.4	ENSP00000358081.4		O95817

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000215

AC:

AN:

232474

Hom.:

AF XY:

0.0000314

AC XY:

AN XY:

127512

show subpopulations

Gnomad AFR exome

AF:

0.0000737

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000381

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1445878

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719284

show subpopulations

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:

0.0000192

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000388

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 29, 2017	Given the absence of this variant in case reports, an uncertain association between missense change and disease, and its low frequency in general population databases, we classify this variant as a variant of uncertain significance. The BAG3 gene belongs to a family of co-chaperones that play a role in anti-apoptosis. BAG3 localizes within the Z-disc and is thought to act as a signaling molecule. Ray Hershberger's group reported BAG3 variants in patients with DCM (Norton et al 2011). In one kindred they performed exome sequencing and copy number variant analysis and identified an 8.7 kbp deletion in BAG3 that was present in all 7 affected family members and absent in 355 controls. They then sequenced exons 2, 3, and 4 in 311 probands with DCM (who had normal sequencing of 15 other DCM genes) and found heterozygous point variants in 7 unrelated probands. This included one frameshift and two nonsense variants. So in their sample, 3/311 cases had a rare nonsense or frameshift. In contrast, 3/~60,000 individuals in ExAC have a nonsense or frameshift variant in BAG3. Segregation data was available for one nonsense variant, which was present in all four affected family members (three siblings and a parent). A knockdown of zebrafish recapitulated the cardiomyopathy and heart failure phenotype. They noted a wide age of onset (21 to 64yo) and varied severity. Arimura et al (2011) analyzed BAG3 in 72 Japanese probands and found missense variants in 2 cases. Chami et al (2014) performed exome sequencing on 44 individuals from families with DCM (unclear if 44 probands or mix of probands and relatives). They found two truncating variants in four families with a LOD score across three families of 3.8. Franaszczyk et al (2014) analyzed BAG3 by qtPCR and sequencing in 90 unrelated DCM patients from Poland. They found rare variants in 6/90 families including three nonsense or frameshift variants and a 17,990 bp deletion removing exons 3-4. These variants segregated with disease in 1-3 additional affected family members in each pedigree. They also noted a slightly later onset and overall lower penetrance in truncating vs. non-truncating variants. All nonsense and frameshift BAG3 variants in ClinVar are classified as likely pathogenic or pathogenic, with submissions from LMM, GeneDx, and Blueprint. In contrast, nearly all of the 44 missense variants in ClinVar submitted by clinical labs are classified as variants of uncertain significance or (likely) benign. There is one likely pathogenic classification for one of the missense variants reported by Norton et al (2011). The data in ClinVar aligns with data from ExAC, which indicates that BAG3 is tolerant of missense change: the number of observed missense variants is higher than that which would be expected (Z= -1.01). This variant is not present in ClinVar. There is no case data for this variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The variant was reported online in 7 of 132,442 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent (as of October 27, 2016) (minor allele frequency of 0.00002643). Specifically, the variant was observed in 4 of 59,473 individuals of European (Non-Finnish) descent, 3 of 23,344 individuals of African descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	Reported in a 38-year-old male with atrial fibrillation and an affected first-degree relative (Goodyer et al., 2019); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 410233; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31638414) -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2023

The p.R45C variant (also known as c.133C>T), located in coding exon 1 of the BAG3 gene, results from a C to T substitution at nucleotide position 133. The arginine at codon 45 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Benign

0.52

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

2.9

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.76

MVP

0.94

MPC

0.48

ClinPred

0.97

GERP RS

3.5

Varity_R

0.65

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over