rs747846089
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_004281.4(BAG3):c.67C>T(p.Pro23Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,598,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P23L) has been classified as Uncertain significance.
Frequency
Consequence
NM_004281.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BAG3 | NM_004281.4 | c.67C>T | p.Pro23Ser | missense_variant | 1/4 | ENST00000369085.8 | |
BAG3 | XM_005270287.2 | c.67C>T | p.Pro23Ser | missense_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BAG3 | ENST00000369085.8 | c.67C>T | p.Pro23Ser | missense_variant | 1/4 | 1 | NM_004281.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152022Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000339 AC: 8AN: 235910Hom.: 0 AF XY: 0.0000388 AC XY: 5AN XY: 128906
GnomAD4 exome AF: 0.0000276 AC: 40AN: 1446924Hom.: 0 Cov.: 31 AF XY: 0.0000236 AC XY: 17AN XY: 719832
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152022Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74252
ClinVar
Submissions by phenotype
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 08, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 23 of the BAG3 protein (p.Pro23Ser). This variant is present in population databases (rs747846089, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary sensory neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 279697). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 12, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2022 | See Variant Classification Assertion Criteria. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 16, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2023 | The p.P23S variant (also known as c.67C>T), located in coding exon 1 of the BAG3 gene, results from a C to T substitution at nucleotide position 67. The proline at codon 23 is replaced by serine, an amino acid with similar properties. This variant was identified in one individual with hereditary sensory neuropathy (Antoniadi T et al. BMC Med. Genet., 2015 Sep;16:84). This variant has also been detected in two cases referred for genetic testing for dilated cardiomyopathy (DCM) and one case with pediatric-onset restrictive cardiomyopathy; however, details were limited (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). This amino acid position is highly 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at