10-119672531-G-A

Position:

• chr10-119672531-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004281.4(BAG3):​c.784G>A​(p.Ala262Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A262V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1659939).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.784G>A	p.Ala262Thr	missense_variant	3/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.784G>A	p.Ala262Thr	missense_variant	3/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.784G>A	p.Ala262Thr	missense_variant	3/4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.610G>A	p.Ala204Thr	missense_variant	4/5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461586 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 262 of the BAG3 protein (p.Ala262Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 21353195). ClinVar contains an entry for this variant (Variation ID: 234983). 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. 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 specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jul 22, 2015

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given there is only minimal case data and the variant has been repeatedly seen with a nonsense variant, we consider this variant a variant of uncertain significance. The variant has been seen in at least one unrelated cases of DCM. There is weak segregation data. It has been observed in two brothers with dilated cardiomyopathy, AV block, Q waves (Norton et al 2011). They were both severely affected and underwent heart transplant in their 40s. These brothers also have a BAG3 p.Tyr233Ter variant, though this was not reported in Norton et al (2011). In silico analysis predicts the variant doesn't negatively affect the protein. The alanine at codon 262 is not conserved across species. Other variants have been reported in association with disease at nearby codons (p.Arg258Trp, HGMD). The variant was reported online in 9 of 60384 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 14th, 2015). Specifically, the variant was observed in 8 of 33,160 Europeans (MAF 0.0001206). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2018

The A262T variant of uncertain significance in the BAG3 gene has been reported previously in association with DCM (Norton et al., 2011). A262T was reported in two brothers with DCM, who each underwent a heart transplantation, and had a family history significant for DCM in their father; however, the father was unavailable for testing (Norton et al., 2011).The A262T variant is not observed in large population cohorts (Lek et al., 2016). The A262T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The p.A262T variant (also known as c.784G>A), located in coding exon 3 of the BAG3 gene, results from a G to A substitution at nucleotide position 784. The alanine at codon 262 is replaced by threonine, an amino acid with similar properties. This variant has been detected in brothers affected with dilated cardiomyopathy (DCM) and who were suspected to have an additional alteration in BAG3 identified (Norton N et al. Am. J. Hum. Genet., 2011 Mar;88:273-82). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.052	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0090	B;.
Vest4		0.17
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0082);.;
MVP		0.97
MPC		0.11
ClinPred		0.43	T
GERP RS		4.0
Varity_R		0.047
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876661343; hg19: chr10-121432043;