BAG3

BAG cochaperone 3, the group of BAG cochaperones

Basic information

Region (hg38): 10:119651379-119677819

Links

ENSG00000151929 ∙ NCBI:9531 ∙ OMIM:603883 ∙ HGNC:939 ∙ Uniprot:O95817 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• myofibrillar myopathy 6 (Supportive), mode of inheritance: AD
• myofibrillar myopathy 6 (Strong), mode of inheritance: AD
• dilated cardiomyopathy 1HH (Definitive), mode of inheritance: AD
• myofibrillar myopathy 6 (Definitive), mode of inheritance: AD
• myofibrillar myopathy 6 (Strong), mode of inheritance: AD
• dilated cardiomyopathy 1HH (Strong), mode of inheritance: AD
• myofibrillar myopathy (Definitive), mode of inheritance: AD
• dilated cardiomyopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiomyopathy, dilated, 1HH; Myopathy, myofibrillar 6	AD	Cardiovascular	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	Cardiovascular; Musculoskeletal; Neurologic	16936253; 19085932; 20301672; 21898660; 21256014; 21353195; 21361913; 21459883; 25208129

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the BAG3 gene.

• Dilated cardiomyopathy 1HH;Myofibrillar myopathy 6 (381 variants)
• Myofibrillar myopathy 6;Dilated cardiomyopathy 1HH (364 variants)
• Cardiovascular phenotype (297 variants)
• not provided (262 variants)
• not specified (106 variants)
• Dilated cardiomyopathy 1HH (80 variants)
• Myofibrillar myopathy 6 (71 variants)
• Cardiomyopathy (23 variants)
• Primary dilated cardiomyopathy (17 variants)
• BAG3-related condition (9 variants)
• Primary familial dilated cardiomyopathy (7 variants)
• Dilated Cardiomyopathy, Dominant (7 variants)
• Inborn genetic diseases (7 variants)
• Myofibrillar Myopathy, Dominant (7 variants)
• Long QT syndrome (3 variants)
• Primary familial hypertrophic cardiomyopathy (3 variants)
• Dilated cardiomyopathy 1A (3 variants)
• Atrial fibrillation (2 variants)
• Hypertrophic cardiomyopathy (2 variants)
• Primary dilated cardiomyopathy;Myocarditis (2 variants)
• Myofibrillar myopathy (1 variants)
• Peripheral neuropathy (1 variants)
• Abnormality of the musculature (1 variants)
• Left ventricular noncompaction (1 variants)
• Elevated circulating creatine kinase concentration (1 variants)
• Familial isolated arrhythmogenic right ventricular dysplasia (1 variants)
• Premature ventricular contraction;Cardiomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the BAG3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	183	3	192
missense	4	2	449	14	2	471
nonsense	32	12	1			45
start loss			2			2
frameshift	33	16	7			56
inframe indel		1	11	2		14
splice donor/acceptor (+/-2bp)		4	1			5
splice region			8	4	1	13
non coding			12	24	18	54
Total	69	35	489	223	23

Highest pathogenic variant AF is 0.00000659

Variants in BAG3

This is a list of pathogenic ClinVar variants found in the BAG3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
10-119651382-A-C		Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH	Conflicting classifications of pathogenicity (Mar 01, 2023)
10-119651383-T-A		Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH	Conflicting classifications of pathogenicity (Mar 01, 2023)
10-119651391-C-A		Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6	Uncertain significance (Jan 13, 2018)
10-119651391-C-T		Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6	Uncertain significance (Jan 13, 2018)
10-119651392-G-C		Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6	Conflicting classifications of pathogenicity (Jun 26, 2018)
10-119651405-C-T		Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH	Conflicting classifications of pathogenicity (Jan 13, 2018)
10-119651468-C-T			Likely benign (Jul 07, 2018)
10-119651521-C-G		Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6;Dilated cardiomyopathy 1HH	Uncertain significance (Nov 20, 2021)
10-119651548-G-T		Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6	Uncertain significance (Jan 13, 2018)
10-119651581-G-A		Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6	Conflicting classifications of pathogenicity (May 01, 2023)
10-119651586-G-A			Benign (Apr 01, 2022)
10-119651589-G-T		Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH	Uncertain significance (Jan 13, 2018)
10-119651590-G-A		Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6	Uncertain significance (Jan 13, 2018)
10-119651626-C-T		not specified	Benign (Sep 02, 2014)
10-119651658-G-A		not specified • Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH	Conflicting classifications of pathogenicity (Jan 13, 2018)
10-119651659-G-A		not specified • Dilated cardiomyopathy 1HH • Myofibrillar myopathy 6	Conflicting classifications of pathogenicity (Sep 21, 2023)
10-119651672-C-T		not specified • Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Apr 27, 2022)
10-119651674-G-T		Dilated cardiomyopathy 1HH	Uncertain significance (Apr 11, 2018)
10-119651676-A-C		Dilated cardiomyopathy 1HH;Myofibrillar myopathy 6	Uncertain significance (Jan 29, 2024)
10-119651677-T-G		Myofibrillar myopathy 6;Dilated cardiomyopathy 1HH	Uncertain significance (Sep 01, 2023)
10-119651680-G-A		Dilated cardiomyopathy 1HH;Myofibrillar myopathy 6 • Cardiovascular phenotype	Uncertain significance (Jul 06, 2023)
10-119651682-G-A		Myofibrillar myopathy 6;Dilated cardiomyopathy 1HH	Uncertain significance (Oct 04, 2023)
10-119651682-G-T		Myofibrillar myopathy 6 • Dilated cardiomyopathy 1HH	Uncertain significance (Jan 12, 2018)
10-119651688-A-G		not specified • Myofibrillar myopathy 6;Dilated cardiomyopathy 1HH • Dilated cardiomyopathy 1HH	Conflicting classifications of pathogenicity (Dec 12, 2023)
10-119651689-C-T		Cardiovascular phenotype	Uncertain significance (May 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BAG3	protein_coding	protein_coding	ENST00000369085	4	26450

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.617	0.383	125743	0	5	125748	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.736	376	338	1.11	0.0000201	3675
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000702	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000264	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Busulfan Pathway, Pharmacodynamics;Apoptosis Modulation and Signaling;Regulation of HSF1-mediated heat shock response;Cellular responses to stress;Cellular responses to external stimuli;Cellular response to heat stress (Consensus)

Recessive Scores

• pRec: 0.211

Intolerance Scores

• loftool: 0.127
• rvis_EVS: 0.11
• rvis_percentile_EVS: 62.14

Haploinsufficiency Scores

• pHI: 0.591
• hipred: Y
• hipred_score: 0.734
• ghis: 0.460

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.441

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Bag3
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); immune system phenotype

Zebrafish Information Network

• Gene name: bag3
• Affected structure: slow muscle cell
• Phenotype tag: abnormal
• Phenotype quality: broken

Gene ontology

• Biological process: autophagosome assembly;protein folding;brain development;extrinsic apoptotic signaling pathway via death domain receptors;negative regulation of striated muscle cell apoptotic process;spinal cord development;cellular response to heat;cellular response to unfolded protein;positive regulation of protein import into nucleus;negative regulation of apoptotic process;muscle cell cellular homeostasis;positive regulation of protein export from nucleus;regulation of catalytic activity;protein stabilization;chaperone-mediated autophagy;aggresome assembly;cellular response to mechanical stimulus;chaperone-mediated protein transport;extrinsic apoptotic signaling pathway in absence of ligand;negative regulation of transcription from RNA polymerase II promoter in response to stress;protein transport along microtubule;regulation of cellular response to heat;negative regulation of protein targeting to mitochondrion;positive regulation of aggrephagy
• Cellular component: stress fiber;nucleus;cytoplasm;cytosol;plasma membrane;aggresome;Z disc;neuron projection;chaperone complex
• Molecular function: adenyl-nucleotide exchange factor activity;protein binding;protein transporter activity;protein-containing complex binding;cadherin binding;dynein intermediate chain binding;chaperone binding