rs752772180
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004281.4(BAG3):c.634C>A(p.His212Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H212H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
BAG3
NM_004281.4 missense
NM_004281.4 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 6.13
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BAG3 | NM_004281.4 | c.634C>A | p.His212Asn | missense_variant | 3/4 | ENST00000369085.8 | |
BAG3 | XM_005270287.2 | c.634C>A | p.His212Asn | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BAG3 | ENST00000369085.8 | c.634C>A | p.His212Asn | missense_variant | 3/4 | 1 | NM_004281.4 | P1 | |
BAG3 | ENST00000450186.1 | c.460C>A | p.His154Asn | missense_variant | 4/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 exome
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3
AN:
1461880
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727242
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2022 | This variant is not present in population databases (gnomAD no frequency). 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. 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 expected to disrupt BAG3 protein function. ClinVar contains an entry for this variant (Variation ID: 548141). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 212 of the BAG3 protein (p.His212Asn). - |
Dilated cardiomyopathy 1HH Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Jul 04, 2018 | The variant p.H212N was characterized as probably pathogenic by multiple prediction tools (PP3 criteria in ACMG Guidelines). It is also absent from population databases (PM2 criteria in ACMG Guidelines). However, in summary, the p.H212N variant can be classified as variant with unknown clinical significance. The p.H212N variant discovered in female patient with early-onset dilatation cardiomyopathy (pediatric DCM) and heart failure. The patient underwent heart transplantation at the age of 19. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MutPred
Gain of loop (P = 0.069);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at