rs761727804
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBS1_SupportingBS2
The NM_004281.4(BAG3):c.1232_1234delGAG(p.Gly411del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00021 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
BAG3
NM_004281.4 disruptive_inframe_deletion
NM_004281.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.54
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_004281.4. Strenght limited to Supporting due to length of the change: 1aa.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00021 (32/152326) while in subpopulation AFR AF= 0.000674 (28/41560). AF 95% confidence interval is 0.000478. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 32 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BAG3 | NM_004281.4 | c.1232_1234delGAG | p.Gly411del | disruptive_inframe_deletion | 4/4 | ENST00000369085.8 | NP_004272.2 | |
BAG3 | XM_005270287.2 | c.1229_1231delGAG | p.Gly410del | disruptive_inframe_deletion | 4/4 | XP_005270344.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BAG3 | ENST00000369085.8 | c.1232_1234delGAG | p.Gly411del | disruptive_inframe_deletion | 4/4 | 1 | NM_004281.4 | ENSP00000358081.4 |
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152208Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251302Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135868
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461874Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 727242
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GnomAD4 genome AF: 0.000210 AC: 32AN: 152326Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20AN XY: 74480
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This variant, c.1232_1234del, results in the deletion of 1 amino acid(s) of the BAG3 protein (p.Gly411del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761727804, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with clinical features of BAG3-related conditions (PMID: 31983221, 32746448). ClinVar contains an entry for this variant (Variation ID: 410228). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 21, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 410228; Landrum et al., 2016); In-frame deletion of one glycine residue and in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31983221) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2024 | The c.1232_1234delGAG variant (also known as p.G411del) is located in coding exon 4 of the BAG3 gene. This variant results from an in-frame GAG deletion at nucleotide positions 1232 to 1234. This results in the in-frame deletion of a glycine residue at codon 411. This variant has been detected in a dilated cardiomyopathy cohort and a healthy control cohort (Mazzarotto F et al. Circulation. 2020 02;141(5):387-398). This variant co-occurred with another variant in a cardiac-related gene in an individual with noncompaction cardiomyopathy (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at