rs3858340

Variant names:

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.1220C>T(p.Pro407Leu) variant causes a missense change. The variant allele was found at a frequency of 0.101 in 1,614,030 control chromosomes in the GnomAD database, including 9,406 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P407S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1340 hom., cov: 31)

Exomes 𝑓: 0.098 ( 8066 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.50

Publications

40 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016813278).

BP6

Variant 10-119676774-C-T is Benign according to our data. Variant chr10-119676774-C-T is described in ClinVar as Benign. ClinVar VariationId is 44776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4 link	c.1220C>T	p.Pro407Leu	missense_variant	Exon 4 of 4	ENST00000369085.8	NP_004272.2	O95817
BAG3	XM_005270287.2 link	c.1217C>T	p.Pro406Leu	missense_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.1220C>T	p.Pro407Leu	missense_variant	Exon 4 of 4	1	NM_004281.4	ENSP00000358081.4		O95817

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18793

AN:

152078

Hom.:

1335

Cov.:

show subpopulations

Gnomad AFR

AF:

0.168

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.0832

Gnomad EAS

AF:

0.260

Gnomad SAS

AF:

0.0827

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0878

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.118

AC:

29552

AN:

251250

AF XY:

0.111

show subpopulations

Gnomad AFR exome

AF:

0.168

Gnomad AMR exome

AF:

0.174

Gnomad ASJ exome

AF:

0.0757

Gnomad EAS exome

AF:

0.266

Gnomad FIN exome

AF:

0.106

Gnomad NFE exome

AF:

0.0862

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.0984

AC:

143895

AN:

1461834

Hom.:

8066

Cov.:

AF XY:

0.0972

AC XY:

70708

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.166

AC:

5568

AN:

33480

American (AMR)

AF:

0.171

AC:

7651

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0810

AC:

2117

AN:

26136

East Asian (EAS)

AF:

0.264

AC:

10461

AN:

39698

South Asian (SAS)

AF:

0.0814

AC:

7023

AN:

86258

European-Finnish (FIN)

AF:

0.106

AC:

5646

AN:

53386

Middle Eastern (MID)

AF:

0.0794

AC:

458

AN:

5766

European-Non Finnish (NFE)

AF:

0.0886

AC:

98568

AN:

1112000

Other (OTH)

AF:

0.106

AC:

6403

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

9117

18234

27351

36468

45585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3852

7704

11556

15408

19260

<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:

0.124

AC:

18816

AN:

152196

Hom.:

1340

Cov.:

AF XY:

0.124

AC XY:

9240

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.167

AC:

6947

AN:

41502

American (AMR)

AF:

0.151

AC:

2305

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0832

AC:

289

AN:

3472

East Asian (EAS)

AF:

0.261

AC:

1353

AN:

5178

South Asian (SAS)

AF:

0.0826

AC:

399

AN:

4832

European-Finnish (FIN)

AF:

0.108

AC:

1141

AN:

10582

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0878

AC:

5974

AN:

68020

Other (OTH)

AF:

0.129

AC:

272

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

825

1650

2475

3300

4125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.104

Hom.:

2076

Bravo

AF:

0.131

TwinsUK

AF:

0.0779

AC:

289

ALSPAC

AF:

0.0898

AC:

346

ESP6500AA

AF:

0.170

AC:

751

ESP6500EA

AF:

0.0877

AC:

754

ExAC

AF:

0.114

AC:

13856

Asia WGS

AF:

0.165

AC:

572

AN:

3478

EpiCase

AF:

0.0842

EpiControl

AF:

0.0835

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Mar 12, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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.Pro407Leu in Exon 04 of BAG3: This variant is not expected to have clinical si gnificance because it has been identified in 17.0% (636/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs3858340). -

Jan 20, 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

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

- -

Myofibrillar myopathy 6

Benign:3

May 28, 2019

Mendelics

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. -

Jun 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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.1220C>T (p.Pro407Leu) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict benign outcome for this variant (Mutation Taster not captured due to low reliability index). This variant was found in 13824/121204 control chromosomes (1012 homozygotes) from ExAC at a frequency of 0.1140556, which is approximately 2920 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), thus this variant is a common benign polymorphism. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. In literature, this variant has been reported in one DCM patient who also carried a rare variant p.I206V and was classified as a known polymorphism (Ruppert_2013). Taken together, this variant is classified as benign. -

Nov 15, 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: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

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

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

4.5

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.21

Sift

Uncertain

0.016

Sift4G

Uncertain

0.0080

Polyphen

0.19

Vest4

0.030

MPC

0.070

ClinPred

0.045

GERP RS

5.7

Varity_R

0.081

gMVP

0.24

Mutation Taster

=98/2

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