rs3858340

Positions:

chr10-119676774-C-T

Variant summary

Our verdict is Benign. Variant got -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. Variant has been reported in ClinVar as 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:16

Conservation

PhyloP100: 4.50

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=0.0016813278).

BP6

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

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/exons	MANE	Protein	UniProt
BAG3	NM_004281.4 linkuse as main transcript	c.1220C>T	p.Pro407Leu	missense_variant	4/4	ENST00000369085.8	NP_004272.2	O95817
BAG3	XM_005270287.2 linkuse as main transcript	c.1217C>T	p.Pro406Leu	missense_variant	4/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 linkuse as main transcript	c.1220C>T	p.Pro407Leu	missense_variant	4/4	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

GnomAD3 exomes

AF:

0.118

AC:

29552

AN:

251250

Hom.:

2129

AF XY:

0.111

AC XY:

15079

AN XY:

135836

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 SAS exome

AF:

0.0789

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

Gnomad4 AFR exome

AF:

0.166

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.0810

Gnomad4 EAS exome

AF:

0.264

Gnomad4 SAS exome

AF:

0.0814

Gnomad4 FIN exome

AF:

0.106

Gnomad4 NFE exome

AF:

0.0886

Gnomad4 OTH exome

AF:

0.106

GnomAD4 genome

AF:

0.124

AC:

18816

AN:

152196

Hom.:

1340

Cov.:

AF XY:

0.124

AC XY:

9240

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.167

Gnomad4 AMR

AF:

0.151

Gnomad4 ASJ

AF:

0.0832

Gnomad4 EAS

AF:

0.261

Gnomad4 SAS

AF:

0.0826

Gnomad4 FIN

AF:

0.108

Gnomad4 NFE

AF:

0.0878

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.0995

Hom.:

1404

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:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 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	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Myofibrillar myopathy 6

Benign:3

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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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.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. -

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

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. -

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

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

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

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

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