rs2234962

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004281.4(BAG3):c.451T>C(p.Cys151Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,424 control chromosomes in the GnomAD database, including 33,563 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C151Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 2112 hom., cov: 33)

Exomes 𝑓: 0.20 ( 31451 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.566

Publications

103 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001447022).

BP6

Variant 10-119670121-T-C is Benign according to our data. Variant chr10-119670121-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4 link	c.451T>C	p.Cys151Arg	missense_variant	Exon 2 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2 link	c.451T>C	p.Cys151Arg	missense_variant	Exon 2 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 link	c.451T>C	p.Cys151Arg	missense_variant	Exon 2 of 4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1 link	c.277T>C	p.Cys93Arg	missense_variant	Exon 3 of 5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22296

AN:

152058

Hom.:

2111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0368

Gnomad AMI

AF:

0.193

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.139

GnomAD2 exomes

AF:

0.173

AC:

43222

AN:

249702

AF XY:

0.181

show subpopulations

Gnomad AFR exome

AF:

0.0354

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.228

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.184

GnomAD4 exome

AF:

0.200

AC:

292948

AN:

1461248

Hom.:

31451

Cov.:

AF XY:

0.202

AC XY:

147111

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.0305

AC:

1021

AN:

33478

American (AMR)

AF:

0.102

AC:

4581

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

5598

AN:

26126

East Asian (EAS)

AF:

0.00111

AC:

AN:

39682

South Asian (SAS)

AF:

0.215

AC:

18505

AN:

86246

European-Finnish (FIN)

AF:

0.223

AC:

11870

AN:

53138

Middle Eastern (MID)

AF:

0.188

AC:

1082

AN:

5766

European-Non Finnish (NFE)

AF:

0.215

AC:

238943

AN:

1111720

Other (OTH)

AF:

0.187

AC:

11304

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

15671

31343

47014

62686

78357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8034

16068

24102

32136

40170

<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:

0.147

AC:

22298

AN:

152176

Hom.:

2112

Cov.:

AF XY:

0.147

AC XY:

10956

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0368

AC:

1526

AN:

41518

American (AMR)

AF:

0.130

AC:

1984

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

738

AN:

3466

East Asian (EAS)

AF:

0.00289

AC:

AN:

5182

South Asian (SAS)

AF:

0.202

AC:

974

AN:

4818

European-Finnish (FIN)

AF:

0.227

AC:

2404

AN:

10592

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.208

AC:

14153

AN:

67984

Other (OTH)

AF:

0.137

AC:

290

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

985

1970

2955

3940

4925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.188

Hom.:

12966

Bravo

AF:

0.133

TwinsUK

AF:

0.210

AC:

777

ALSPAC

AF:

0.210

AC:

808

ESP6500AA

AF:

0.0414

AC:

182

ESP6500EA

AF:

0.207

AC:

1782

ExAC

AF:

0.175

AC:

21195

Asia WGS

AF:

0.0740

AC:

260

AN:

3478

EpiCase

AF:

0.210

EpiControl

AF:

0.208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

PreventionGenetics, part of Exact Sciences

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 12, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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.Cys151Arg in Exon 02 of BAG3: This variant is not expected to have clinical si gnificance because it has been identified in 20.5% (1437/7016) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2234962). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Aug 11, 2020

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Myofibrillar myopathy 6

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype

Benign:1

Jun 19, 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

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

PhyloP100

0.57

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.7

N;D

REVEL

Benign

0.28

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.0080

D;T

Polyphen

0.66

P;.

Vest4

0.20

MPC

0.50

ClinPred

0.032

GERP RS

0.064

Varity_R

0.33

gMVP

0.42

Mutation Taster

=81/19

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