rs397514506
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_004281.4(BAG3):c.652C>T(p.Arg218Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R218Q) has been classified as Likely benign.
Frequency
Consequence
NM_004281.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BAG3 | NM_004281.4 | c.652C>T | p.Arg218Trp | missense_variant | 3/4 | ENST00000369085.8 | |
BAG3 | XM_005270287.2 | c.652C>T | p.Arg218Trp | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BAG3 | ENST00000369085.8 | c.652C>T | p.Arg218Trp | missense_variant | 3/4 | 1 | NM_004281.4 | P1 | |
BAG3 | ENST00000450186.1 | c.478C>T | p.Arg160Trp | missense_variant | 4/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251270Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135878
GnomAD4 exome AF: 0.0000540 AC: 79AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727242
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74476
ClinVar
Submissions by phenotype
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 05, 2021 | - - |
Dilated cardiomyopathy 1HH Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2011 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 15, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2023 | The p.R218W variant (also known as c.652C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a Japanese proband, diagnosed with dilated cardiomyopathy (DCM) at age 73, who also had three affected siblings. This alteration was shown to disrupt Z-disc assembly in cultured cells; however, the physiological relevance of this finding is uncertain (Arimura T et al. Hum. Mutat., 2011 Dec;32:1481-91). This variant was also detected in a individual with skeletal muscle weakness, and in a stillbirth case where it co-occurred with a variant in a different cardiac-related gene (Wu L et al. Can J Neurol Sci. 2018 05;45(3):262-268; Sahlin E et al. PLoS ONE. 2019 Jan;14(1):e0210017). This variant has also been detected in a cohorts not selected for the presence of disease; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Kars ME et al. Proc Natl Acad Sci U S A. 2021 09;118(36)). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at