rs196295

Positions:

• chr10-119676850-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004281.4(BAG3):​c.1296A>G​(p.Val432=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,613,978 control chromosomes in the GnomAD database, including 478,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43760 hom., cov: 32)
  • Exomes 𝑓: 0.77 (435129 hom.)
• Consequence: BAG3 NM_004281.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.550

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 10-119676850-A-G is Benign according to our data. Variant chr10-119676850-A-G is described in ClinVar as [Benign]. Clinvar id is 44777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119676850-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.1296A>G	p.Val432=	synonymous_variant	4/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.1293A>G	p.Val431=	synonymous_variant	4/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.1296A>G	p.Val432=	synonymous_variant	4/4	1	NM_004281.4	ENSP00000358081	P1

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114888 AN: 152038 Hom.: 43725 Cov.: 32

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.819

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.784

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.738 AC: 185417 AN: 251322 Hom.: 69356 AF XY: 0.744 AC XY: 101023 AN XY: 135856

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.642

Gnomad ASJ exome AF: 0.818

Gnomad EAS exome AF: 0.515

Gnomad SAS exome AF: 0.764

Gnomad FIN exome AF: 0.742

Gnomad NFE exome AF: 0.784

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.770 AC: 1125074 AN: 1461822 Hom.: 435129 Cov.: 85 AF XY: 0.770 AC XY: 560117 AN XY: 727210

Gnomad4 AFR exome AF: 0.749

Gnomad4 AMR exome AF: 0.653

Gnomad4 ASJ exome AF: 0.818

Gnomad4 EAS exome AF: 0.518

Gnomad4 SAS exome AF: 0.765

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 0.785

Gnomad4 OTH exome AF: 0.764

GnomAD4 genome AF: 0.756 AC: 114978 AN: 152156 Hom.: 43760 Cov.: 32 AF XY: 0.752 AC XY: 55920 AN XY: 74384

Gnomad4 AFR AF: 0.755

Gnomad4 AMR AF: 0.723

Gnomad4 ASJ AF: 0.819

Gnomad4 EAS AF: 0.520

Gnomad4 SAS AF: 0.737

Gnomad4 FIN AF: 0.738

Gnomad4 NFE AF: 0.784

Gnomad4 OTH AF: 0.746

Alfa AF: 0.779 Hom.: 71592

Bravo AF: 0.752

Asia WGS AF: 0.640 AC: 2227 AN: 3478

EpiCase AF: 0.788

EpiControl AF: 0.789

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Val432Val in Exon 04 of BAG3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 24.3% (909/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs196295). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Myofibrillar myopathy 6 Benign:3

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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2017	Variant summary: The BAG3 c.1296A>G (p.Val432Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESEfinder predicts that it affects binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 89871/121300 control chromosomes (33720 homozygotes) from ExAC at a frequency of 0.7408986, which is approximately 18967 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), thus this variant is a very common benign polymorphism and allele G the wildtype allele at this position. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals in literature. Taken together, this variant is classified as benign. -

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

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.6
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs196295; hg19: chr10-121436362; COSMIC: COSV64841992; COSMIC: COSV64841992;