BAG3
protein-codingBAG cochaperone 3, the group of BAG cochaperones
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013479
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013479
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013061
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013479
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018943
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0018943
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0013061
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013061
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013061
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015362
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0018894
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0976227
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013479
Submitter: ClinGen
BAG3 was originally evaluated for DCM by ClinGen DCM GCEP on September 24, 2020. Evidence of the association of this gene with DCM was re-evaluated on 04/09/2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein. BAG3 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2011 (Norton et al., 2011, PMID: 21353195). At least 16 unique variants including missense, in-frame indel, nonsense and frameshift variants, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data and experimental data. Variants in this gene have been reported in at least 20 probands in 8 primary publications (PMIDs 21353195, 25008357, 25448463, 24623017, 27391596, 28211974, 30442290, 31983221). Variants in this gene segregate with disease in >100 additional family members. This gene-disease relationship has been studied in at least one case-control study (PMID 31983221) at the aggregate variant level, where BAG3 truncating variants were enriched in two DCM cohorts vs primary and ExAC control populations. The reported etiologic fraction for truncating variants was 0.98 and >0.99 for the primary and secondary cohorts respectively. In addition, this gene-disease association is supported by multiple animal models (mouse and zebrafish), human iPS cell culture models, in vitro functional assays, and expression studies. BAG3 was shown to be expressed in human and mouse heart tissues (Homma et al., 2006, PMID: 16936253). BAG3 protein levels were noted to be reduced in heart failure patients and individuals with BAG3 genetic variants (Feldman et al., 2014, PMID: 24623017 and Toro et al., 2016, PMID: 27391596). Heterozygous cardiomyocyte-specific BAG3 knockout or BAG3 E455K knock-in mouse models both developed DCM phenotypes (Fang et al., 2017, PMID: 28737513 and Myers et al., 2018, PMID: 29323723). Additional evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached.BAG3 has also been curated by the General Gene Curation Expert Panel for myofibrillar myopathy (Definitive, 12/18/2016). In summary, BAG3 is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Dilated Cardiomyopathy Working Group on September 24, 2020 (SOP Version 7). This written summary was updated on 04/09/2025 and approved by the DCM GCEP on 05/30/2025.
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: In Dilated cardiomyopathy, surveillance (eg, with echocardiogram and electocardiogram) may allow early detection and management of manifestations, which may be beneficial; In Myofibrillar myopathy, individuals typically present with slowly progressive weakness, and a significant proportion of individuals demonstrate cardiomyopathy, such that surveillance for arrhythmia or conduction defects may allow early treatment (eg, pacemaker, ICD); Cardiac transplantation may be necessary individuals with severe forms of cardiomyopathy; Heart transplant has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BAG3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004281.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 300 | 8 | 310 | ||
| missense | 5 | 5 | 696 | 80 | 2 | 788 |
| nonsense | 35 | 24 | 5 | 64 | ||
| start loss | 2 | 2 | ||||
| frameshift | 62 | 28 | 16 | 106 | ||
| splice donor/acceptor (+/-2bp) | 3 | 5 | 1 | 9 | ||
| Total | 105 | 62 | 722 | 380 | 10 | 1279 |
Highest pathogenic variant AF is 0.000019153602
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004272.2 | 4 | MANE Select | |
| Ensembl | ENSP00000358081.4 | 4 | MANE Select | |
| Ensembl | ENSP00000410036.1 | 4 | Standard | |
| Ensembl | ENSP00000560036.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| bag3 | Danio rerio | Structure: slow muscle cell Quality: broken abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Busulfan Pathway, Pharmacodynamics
- Apoptosis Modulation and Signaling
- Regulation of HSF1-mediated heat shock response
- Cellular responses to stress
- Cellular responses to external stimuli
Biological Process
- autophagosome assembly
- protein folding
- brain development
- extrinsic apoptotic signaling pathway via death domain receptors
- negative regulation of striated muscle cell apoptotic process
Molecular Function
- adenyl-nucleotide exchange factor activity
- protein binding
- protein transporter activity
- protein-containing complex binding
- cadherin binding
Cellular Component
- stress fiber
- nucleus
- cytoplasm
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000369085
- Coding exons
- 4
- Length
- 26450
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125748
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.736 | 376 | 338 | 1.11 | 0.0000201 | 3675 |
| Missense (PolyPhen) | 113 | 102.62 | 1.1012 | 1022 | ||
| Synonymous | -0.128 | 144 | 142 | 1.01 | 0.00000903 | 1258 |
| Loss of Function | 3.37 | 4 | 20.5 | 0.195 | 0.00000133 | 198 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000070 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release. Nucleotide release is mediated via its binding to the nucleotide-binding domain (NBD) of HSPA8/HSC70 where as the substrate release is mediated via its binding to the substrate-binding domain (SBD) of HSPA8/HSC70 (PubMed:9873016, PubMed:27474739). Has anti-apoptotic activity (PubMed:10597216). Plays a role in the HSF1 nucleocytoplasmic transport (PubMed:26159920). {ECO:0000269|PubMed:10597216, ECO:0000269|PubMed:24318877, ECO:0000269|PubMed:26159920, ECO:0000269|PubMed:27474739, ECO:0000269|PubMed:9873016}.;
- Disease
- DISEASE: Myopathy, myofibrillar, 6 (MFM6) [MIM:612954]: A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM6 is characterized by early- onset of severe, progressive, diffuse muscle weakness associated with cardiomyopathy, severe respiratory insufficiency during adolescence, and a rigid spine in some patients. {ECO:0000269|PubMed:19085932, ECO:0000269|PubMed:21361913, ECO:0000269|PubMed:21898660}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1HH (CMD1HH) [MIM:613881]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:21353195, ECO:0000269|PubMed:21459883, ECO:0000269|PubMed:21898660}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.211
Intolerance Scores
- LoFtool
- 0.127
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 62.14
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.441
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |