rs35434411

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004281.4(BAG3):c.212G>A(p.Arg71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,614,130 control chromosomes in the GnomAD database, including 697 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R71L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 38 hom., cov: 33)

Exomes 𝑓: 0.027 ( 659 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 1.13

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=0.0019952059).

BP6

Variant 10-119669882-G-A is Benign according to our data. Variant chr10-119669882-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119669882-G-A is described in Lovd as [Likely_benign]. Variant chr10-119669882-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0202 (3078/152282) while in subpopulation NFE AF= 0.0317 (2154/68006). AF 95% confidence interval is 0.0306. There are 38 homozygotes in gnomad4. There are 1456 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3078 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4 link	c.212G>A	p.Arg71Gln	missense_variant	2/4	ENST00000369085.8	NP_004272.2	O95817
BAG3	XM_005270287.2 link	c.212G>A	p.Arg71Gln	missense_variant	2/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 link	c.212G>A	p.Arg71Gln	missense_variant	2/4	1	NM_004281.4	ENSP00000358081.4		O95817
BAG3	ENST00000450186.1 link	c.38G>A	p.Arg13Gln	missense_variant	3/5	5		ENSP00000410036.1		C9JFK9

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

3079

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00538

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0335

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0317

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0199

AC:

5005

AN:

251300

Hom.:

AF XY:

0.0200

AC XY:

2718

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00989

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00340

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.0311

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0270

AC:

39502

AN:

1461848

Hom.:

659

Cov.:

AF XY:

0.0263

AC XY:

19152

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00415

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.00562

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00379

Gnomad4 FIN exome

AF:

0.0349

Gnomad4 NFE exome

AF:

0.0316

Gnomad4 OTH exome

AF:

0.0219

GnomAD4 genome

AF:

0.0202

AC:

3078

AN:

152282

Hom.:

Cov.:

AF XY:

0.0196

AC XY:

1456

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00537

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0335

Gnomad4 NFE

AF:

0.0317

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0260

Hom.:

Bravo

AF:

0.0179

TwinsUK

AF:

0.0278

AC:

103

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0326

AC:

280

ExAC

AF:

0.0201

AC:

2443

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0269

EpiControl

AF:

0.0275

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Arg71Gln in Exon 02 of BAG3: This variant is not expected to have clinical sig nificance because it has been identified in 3.4% (237/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35434411). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 01, 2016	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2017	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2017	Variant summary: The BAG3 c.212G>A (p.Arg71Gln) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2442/121378 control chromosomes (35 homozygotes) at a frequency of 0.020119, which is approximately 515 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as benign. To our knowledge, this variant t has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Myofibrillar myopathy 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 14, 2022

- -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Dilated cardiomyopathy 1HH

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

0.071

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

0.38

N;N

REVEL

Benign

0.072

Sift

Benign

0.49

T;T

Sift4G

Benign

0.89

T;T

Polyphen

0.018

B;.

Vest4

0.068

MPC

0.091

ClinPred

0.0079

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.090

gMVP

0.33

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