rs141355480
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004281.4(BAG3):c.230C>T(p.Pro77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,614,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P77P) has been classified as Benign.
Frequency
Consequence
NM_004281.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000309 AC: 47AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000259 AC: 65AN: 251396Hom.: 1 AF XY: 0.000228 AC XY: 31AN XY: 135884
GnomAD4 exome AF: 0.000313 AC: 458AN: 1461880Hom.: 1 Cov.: 32 AF XY: 0.000294 AC XY: 214AN XY: 727240
GnomAD4 genome AF: 0.000309 AC: 47AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74482
ClinVar
Submissions by phenotype
not provided Benign:7
This variant is associated with the following publications: (PMID: 27042682) -
- -
- -
- -
- -
BAG3: BP4, BS2 -
- -
not specified Benign:3
Pro77Leu in exon 2 of BAG3: This variant is not expected to have clinical signif icance due to a lack of conservation across species, including mammals. Of note, >45 mammals and other species have a leucine (Leu) at this position despite hig h nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identi fied in 5/8600 European American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs141355480). -
- -
Variant summary: BAG3 c.230C>T (p.Pro77Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 251396 control chromosomes, predominantly at a frequency of 0.00047 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in BAG3 causing Dilated Cardiomyopathy phenotype (3.9e-05), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.230C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Cardiomyopathy Benign:2
- -
- -
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Benign:1
- -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at