rs61756328

Positions:

chr10-119670133-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004281.4(BAG3):c.463G>A(p.Ala155Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,612,584 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. A155V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0032 ( 19 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 2.34

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004027009).

BP6

Variant 10-119670133-G-A is Benign according to our data. Variant chr10-119670133-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44784.We mark this variant Likely_benign, oryginal submissions are: {Benign=9, Uncertain_significance=1, Likely_benign=4}. Variant chr10-119670133-G-A is described in Lovd as [Benign]. Variant chr10-119670133-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (365/152280) while in subpopulation NFE AF= 0.00354 (241/68030). AF 95% confidence interval is 0.00318. There are 4 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 365 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4 linkuse as main transcript	c.463G>A	p.Ala155Thr	missense_variant	2/4	ENST00000369085.8
BAG3	XM_005270287.2 linkuse as main transcript	c.463G>A	p.Ala155Thr	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8 linkuse as main transcript	c.463G>A	p.Ala155Thr	missense_variant	2/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1 linkuse as main transcript	c.289G>A	p.Ala97Thr	missense_variant	3/5	5

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

366

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00356

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00291

AC:

719

AN:

247498

Hom.:

AF XY:

0.00290

AC XY:

390

AN XY:

134438

show subpopulations

Gnomad AFR exome

AF:

0.000645

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000981

Gnomad FIN exome

AF:

0.00174

Gnomad NFE exome

AF:

0.00369

Gnomad OTH exome

AF:

0.00363

GnomAD4 exome

AF:

0.00316

AC:

4619

AN:

1460304

Hom.:

Cov.:

AF XY:

0.00316

AC XY:

2292

AN XY:

726360

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.0172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000789

Gnomad4 FIN exome

AF:

0.00171

Gnomad4 NFE exome

AF:

0.00334

Gnomad4 OTH exome

AF:

0.00335

GnomAD4 genome

AF:

0.00240

AC:

365

AN:

152280

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00354

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00346

Hom.:

Bravo

AF:

0.00243

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00311

AC:

ExAC

AF:

0.00288

AC:

349

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00450

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 23, 2017	p.Ala155Thr in exon 2 of BAG3: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, wallaby, opossum, and platypus have a threonine (Thr) at this position despi te high nearby amino acid conservation. Computational analyses (AlignGVGD, PolyP hen2, SIFT) do not suggest a high likelihood of impact to the protein. In additi on, it has been identified in 0.5% (294/63478) of European (Non-Finnish) chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.orgdb SNP; rs61756328). -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	BAG3: BP4, BS1, BS2 -
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.463G>A (p.Ala155Thr) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict benign outcome for this variant. This variant was found in 352/117428 control chromosomes (4 homozygotes) from ExAC and literature at a frequency of 0.0029976, which is approximately 77 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 classified this variant as benign/likely benign. It is also regarded as benign in the literature (Ng_2013). 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. -

Dilated cardiomyopathy 1HH

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 06, 2023

- -

Myofibrillar myopathy 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 15, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2017

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

0.068

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.050

T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

0.56

N;N

REVEL

Benign

0.071

Sift

Benign

0.80

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.097

MVP

0.71

MPC

0.084

ClinPred

0.0051

GERP RS

1.7

Varity_R

0.035

gMVP

0.19

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