rs61756328

Variant names:

• chr10-119670133-G-A
• rs61756328
• NM_004281.4:c.463G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 17/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 2.34
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1HH

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen
• myofibrillar myopathy 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-tooth disease, axonal, type 2JJ

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• distal hereditary motor neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 44784.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 365 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.463G>A	p.Ala155Thr	missense_variant	Exon 2 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.463G>A	p.Ala155Thr	missense_variant	Exon 2 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.463G>A	p.Ala155Thr	missense_variant	Exon 2 of 4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.289G>A	p.Ala97Thr	missense_variant	Exon 3 of 5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152162 Hom.: 4 Cov.: 33

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

GnomAD2 exomes AF: 0.00291 AC: 719 AN: 247498 AF XY: 0.00290

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 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.: 19 Cov.: 34 AF XY: 0.00316 AC XY: 2292 AN XY: 726360

African (AFR) AF: 0.000627 AC: 21 AN: 33476

American (AMR) AF: 0.00139 AC: 62 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 449 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000789 AC: 68 AN: 86232

European-Finnish (FIN) AF: 0.00171 AC: 90 AN: 52706

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5764

European-Non Finnish (NFE) AF: 0.00334 AC: 3708 AN: 1111312

Other (OTH) AF: 0.00335 AC: 202 AN: 60332

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152280 Hom.: 4 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74462

African (AFR) AF: 0.000337 AC: 14 AN: 41528

American (AMR) AF: 0.00137 AC: 21 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00354 AC: 241 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00334 Hom.: 3

Bravo AF: 0.00243

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ExAC AF: 0.00288 AC: 349

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00450

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Jan 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jul 28, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 10, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

May 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BAG3: BP4, BS1, BS2 -

Dilated cardiomyopathy 1HH Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 06, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myofibrillar myopathy 6 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Benign:1

Jun 15, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 01, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.77
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N;.
PhyloP100		2.3
PrimateAI	Benign	0.28	T
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	T
GERP RS		1.7
Varity_R		0.035
gMVP		0.19
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs61756328; hg19: chr10-121429645;