rs196295

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004281.4(BAG3):c.1296A>G(p.Val432Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,613,978 control chromosomes in the GnomAD database, including 478,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 43760 hom., cov: 32)

Exomes 𝑓: 0.77 ( 435129 hom. )

Consequence

BAG3
NM_004281.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.550

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1HH
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
myofibrillar myopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen
myofibrillar myopathy 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-tooth disease, axonal, type 2JJ
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
distal hereditary motor neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BAG3 links:

ENSG00000295480 (HGNC:):

ENSG00000295480 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 10-119676850-A-G is Benign according to our data. Variant chr10-119676850-A-G is described in ClinVar as Benign. ClinVar VariationId is 44777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4 link	c.1296A>G	p.Val432Val	synonymous_variant	Exon 4 of 4	ENST00000369085.8	NP_004272.2	O95817
BAG3	XM_005270287.2 link	c.1293A>G	p.Val431Val	synonymous_variant	Exon 4 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 link	c.1296A>G	p.Val432Val	synonymous_variant	Exon 4 of 4	1	NM_004281.4	ENSP00000358081.4		O95817

Frequencies

GnomAD3 genomes

AF:

0.756

AC:

114888

AN:

152038

Hom.:

43725

Cov.:

show subpopulations

Gnomad AFR

AF:

0.755

Gnomad AMI

AF:

0.623

Gnomad AMR

AF:

0.723

Gnomad ASJ

AF:

0.819

Gnomad EAS

AF:

0.519

Gnomad SAS

AF:

0.737

Gnomad FIN

AF:

0.738

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.784

Gnomad OTH

AF:

0.749

GnomAD2 exomes

AF:

0.738

AC:

185417

AN:

251322

AF XY:

0.744

show subpopulations

Gnomad AFR exome

AF:

0.753

Gnomad AMR exome

AF:

0.642

Gnomad ASJ exome

AF:

0.818

Gnomad EAS exome

AF:

0.515

Gnomad FIN exome

AF:

0.742

Gnomad NFE exome

AF:

0.784

Gnomad OTH exome

AF:

0.761

GnomAD4 exome

AF:

0.770

AC:

1125074

AN:

1461822

Hom.:

435129

Cov.:

AF XY:

0.770

AC XY:

560117

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.749

AC:

25063

AN:

33480

American (AMR)

AF:

0.653

AC:

29185

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.818

AC:

21371

AN:

26136

East Asian (EAS)

AF:

0.518

AC:

20572

AN:

39700

South Asian (SAS)

AF:

0.765

AC:

66000

AN:

86258

European-Finnish (FIN)

AF:

0.742

AC:

39587

AN:

53368

Middle Eastern (MID)

AF:

0.801

AC:

4619

AN:

5768

European-Non Finnish (NFE)

AF:

0.785

AC:

872519

AN:

1111994

Other (OTH)

AF:

0.764

AC:

46158

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

18177

36354

54532

72709

90886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20586

41172

61758

82344

102930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.756

AC:

114978

AN:

152156

Hom.:

43760

Cov.:

AF XY:

0.752

AC XY:

55920

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.755

AC:

31330

AN:

41482

American (AMR)

AF:

0.723

AC:

11054

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.819

AC:

2839

AN:

3468

East Asian (EAS)

AF:

0.520

AC:

2697

AN:

5182

South Asian (SAS)

AF:

0.737

AC:

3558

AN:

4826

European-Finnish (FIN)

AF:

0.738

AC:

7810

AN:

10584

Middle Eastern (MID)

AF:

0.782

AC:

230

AN:

294

European-Non Finnish (NFE)

AF:

0.784

AC:

53319

AN:

68010

Other (OTH)

AF:

0.746

AC:

1574

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1407

2814

4222

5629

7036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.774

Hom.:

121704

Bravo

AF:

0.752

Asia WGS

AF:

0.640

AC:

2227

AN:

3478

EpiCase

AF:

0.788

EpiControl

AF:

0.789

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val432Val in Exon 04 of BAG3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 24.3% (909/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs196295). -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Myofibrillar myopathy 6

Benign:3

Jun 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Aug 04, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The BAG3 c.1296A>G (p.Val432Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESEfinder predicts that it affects binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 89871/121300 control chromosomes (33720 homozygotes) from ExAC at a frequency of 0.7408986, which is approximately 18967 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), thus this variant is a very common benign polymorphism and allele G the wildtype allele at this position. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals in literature. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1HH

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Mar 11, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.6

(source)

DANN

Benign

0.74

PhyloP100

-0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over