rs548032105
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The ENST00000369085.8(BAG3):c.781C>T(p.Arg261Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R261Q) has been classified as Likely benign.
Frequency
Consequence
ENST00000369085.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BAG3 | NM_004281.4 | c.781C>T | p.Arg261Trp | missense_variant | 3/4 | ENST00000369085.8 | NP_004272.2 | |
BAG3 | XM_005270287.2 | c.781C>T | p.Arg261Trp | missense_variant | 3/4 | XP_005270344.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BAG3 | ENST00000369085.8 | c.781C>T | p.Arg261Trp | missense_variant | 3/4 | 1 | NM_004281.4 | ENSP00000358081 | P1 | |
BAG3 | ENST00000450186.1 | c.607C>T | p.Arg203Trp | missense_variant | 4/5 | 5 | ENSP00000410036 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250410Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135412
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461512Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33AN XY: 727018
GnomAD4 genome AF: 0.0000459 AC: 7AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74486
ClinVar
Submissions by phenotype
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 18, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 261 of the BAG3 protein (p.Arg261Trp). This variant is present in population databases (rs548032105, gnomAD 0.02%). This missense change has been observed in individual(s) with BAG3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 162779). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAG3 protein function with a negative predictive value of 80%. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 11, 2020 | The p.R261W variant (also known as c.781C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 781. The arginine at codon 261 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual with hypertrophic cardiomyopathy (HCM) who had variants in other cardiac genes (Forleo C et al. PLoS ONE, 2017 Jul;12:e0181842). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2014 | Arg261Trp in exon 3 of BAG3: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , 9 mammals have a tryptophan (Trp) at this position despite high nearby amino a cid conservation. In addition, computational prediction tools do not suggest a h igh likelihood of impact to the protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at