BAG3

BAG cochaperone 3, the group of BAG cochaperones

Basic information

Region (hg38): 10:119651380-119677819

Links

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

Phenotypes

GenCC

Source: genCC

• myofibrillar myopathy 6 (Strong), mode of inheritance: AD
• distal hereditary motor neuropathy (Limited), mode of inheritance: AD
• Charcot-Marie-tooth disease, axonal, type 2JJ (Limited), mode of inheritance: AD
• dilated cardiomyopathy (Definitive), mode of inheritance: AD
• myofibrillar myopathy (Definitive), mode of inheritance: Unknown
• myofibrillar myopathy 6 (Strong), mode of inheritance: AD
• dilated cardiomyopathy 1HH (Strong), mode of inheritance: AD
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• myofibrillar myopathy 6 (Supportive), mode of inheritance: AD
• dilated cardiomyopathy 1HH (Definitive), mode of inheritance: AD
• myofibrillar myopathy (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; 28754666; 31853710; 37907725

ClinVar

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

• Dilated_cardiomyopathy_1HH (1130 variants)
• Myofibrillar_myopathy_6 (1118 variants)
• Cardiovascular_phenotype (467 variants)
• not_provided (313 variants)
• not_specified (124 variants)
• BAG3-related_disorder (31 variants)
• Cardiomyopathy (23 variants)
• Primary_dilated_cardiomyopathy (21 variants)
• Primary_familial_dilated_cardiomyopathy (7 variants)
• Long_QT_syndrome (3 variants)
• Primary_familial_hypertrophic_cardiomyopathy (3 variants)
• Atrial_fibrillation (2 variants)
• Hypertrophic_cardiomyopathy (2 variants)
• Myocarditis (2 variants)
• Premature_ventricular_contraction (1 variants)
• Abnormality_of_the_musculature (1 variants)
• Peripheral_neuropathy (1 variants)
• Elevated_circulating_creatine_kinase_concentration (1 variants)
• Left_ventricular_noncompaction_1 (1 variants)
• See_cases (1 variants)
• Myofibrillar_myopathy (1 variants)
• Familial_isolated_arrhythmogenic_right_ventricular_dysplasia (1 variants)
• Neuronopathy,_distal_hereditary_motor,_autosomal_dominant_15 (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. These statistics are base on transcript: NM_000004281.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	290	8	300
missense	5	5	681	72	3	766
nonsense	38	20	5			63
start loss			2			2
frameshift	56	25	17			98
splice donor/acceptor (+/-2bp)	1	7	1			9
Total	100	57	708	362	11

Highest pathogenic variant AF is 0.000019153602

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
		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

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

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