rs2234962

chr10-119670121-T-C

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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. C151H) 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:15

Conservation

PhyloP100: 0.566

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 44783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119670121-T-C is described in Lovd as [Benign].

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/exons	MANE	UniProt
BAG3	NM_004281.4 linkuse as main transcript	c.451T>C	p.Cys151Arg	missense_variant	2/4	ENST00000369085.8
BAG3	XM_005270287.2 linkuse as main transcript	c.451T>C	p.Cys151Arg	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8 linkuse as main transcript	c.451T>C	p.Cys151Arg	missense_variant	2/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1 linkuse as main transcript	c.277T>C	p.Cys93Arg	missense_variant	3/5	5

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

GnomAD3 exomes

AF:

0.173

AC:

43222

AN:

249702

Hom.:

4544

AF XY:

0.181

AC XY:

24501

AN XY:

135268

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 SAS exome

AF:

0.210

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

Gnomad4 AFR exome

AF:

0.0305

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.214

Gnomad4 EAS exome

AF:

0.00111

Gnomad4 SAS exome

AF:

0.215

Gnomad4 FIN exome

AF:

0.223

Gnomad4 NFE exome

AF:

0.215

Gnomad4 OTH exome

AF:

0.187

GnomAD4 genome

AF:

0.147

AC:

22298

AN:

152176

Hom.:

2112

Cov.:

AF XY:

0.147

AC XY:

10956

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0368

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.213

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.202

Gnomad4 FIN

AF:

0.227

Gnomad4 NFE

AF:

0.208

Gnomad4 OTH

AF:

0.137

Alfa

AF:

0.196

Hom.:

7063

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2014	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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	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). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Myofibrillar myopathy 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Dilated cardiomyopathy 1HH

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

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

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;.

MutationTaster

Benign

2.4e-7

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

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