rs397514506

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_004281.4(BAG3):c.652C>T(p.Arg218Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:1

Conservation

PhyloP100: 1.17

Publications

18 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28359956).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000054 (79/1461884) while in subpopulation EAS AF = 0.00073 (29/39700). AF 95% confidence interval is 0.000522. There are 0 homozygotes in GnomAdExome4. There are 45 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4 link	c.652C>T	p.Arg218Trp	missense_variant	Exon 3 of 4	ENST00000369085.8	NP_004272.2	O95817
BAG3	XM_005270287.2 link	c.652C>T	p.Arg218Trp	missense_variant	Exon 3 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 link	c.652C>T	p.Arg218Trp	missense_variant	Exon 3 of 4	1	NM_004281.4	ENSP00000358081.4		O95817

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000836

AC:

AN:

251270

AF XY:

0.0000662

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.000730

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112012

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000657

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41572

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000603

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 15, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in a patient with DCM and in a patient with muscle disease in the published literature (PMID: 23861362, 29382405); Published functional studies suggest a damaging effect by impairing Z-disc assembly and increasing sensitivity to apoptosis (PMID: 21898660); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29382405, 34426522, 32093037, 30615648, 33658040, 21898660, 23861362, 37216087) -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Uncertain:1Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1HH

Pathogenic:1

Dec 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Cardiovascular phenotype

Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R218W variant (also known as c.652C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a Japanese proband, diagnosed with dilated cardiomyopathy (DCM) at age 73, who also had three affected siblings. This alteration was shown to disrupt Z-disc assembly in cultured cells; however, the physiological relevance of this finding is uncertain (Arimura T et al. Hum. Mutat., 2011 Dec;32:1481-91). This variant was also detected in a individual with skeletal muscle weakness, and in a stillbirth case where it co-occurred with a variant in a different cardiac-related gene (Wu L et al. Can J Neurol Sci. 2018 05;45(3):262-268; Sahlin E et al. PLoS ONE. 2019 Jan;14(1):e0210017). This variant has also been detected in a cohorts not selected for the presence of disease; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Kars ME et al. Proc Natl Acad Sci U S A. 2021 09;118(36)). This amino acid position is well 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. -

Familial isolated arrhythmogenic right ventricular dysplasia

Uncertain:1

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.077

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

1.2

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.45

Sift

Benign

0.092

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;.

Vest4

0.73

MutPred

0.48

Loss of disorder (P = 0.0049);.;

MVP

0.95

MPC

0.42

ClinPred

0.37

GERP RS

5.2

Varity_R

0.14

gMVP

0.32

Mutation Taster

=34/66

disease causing

(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