rs766766600

Variant names:

• chr10-119672304-C-T
• rs766766600
• NM_004281.4:c.557C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004281.4(BAG3):​c.557C>T​(p.Ala186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A186P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.55
• Publications: 0 publications found

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]

BAG3 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1HH

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen
• myofibrillar myopathy 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-tooth disease, axonal, type 2JJ

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• distal hereditary motor neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000295480 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.186032).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	NM_004281.4	MANE Select	c.557C>T	p.Ala186Val	missense	Exon 3 of 4	NP_004272.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	ENST00000369085.8	TSL:1 MANE Select	c.557C>T	p.Ala186Val	missense	Exon 3 of 4	ENSP00000358081.4
	BAG3	ENST00000450186.1	TSL:5	c.383C>T	p.Ala128Val	missense	Exon 4 of 5	ENSP00000410036.1
	ENSG00000295480	ENST00000730378.1		n.406-1299G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249584 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Sep 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 186 of the BAG3 protein (p.Ala186Val). This variant is present in population databases (rs766766600, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. ClinVar contains an entry for this variant (Variation ID: 471802). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

not provided Uncertain:1

Jun 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Cardiovascular phenotype Uncertain:1

Mar 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A186V variant (also known as c.557C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 557. The alanine at codon 186 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.046
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.16
Sift	Benign	0.39	T
Sift4G	Benign	0.50	T
Polyphen		0.14	B
Vest4		0.43
MutPred		0.28		Gain of catalytic residue at A186 (P = 0.0186)
MVP		0.79
MPC		0.38
ClinPred		0.69	D
GERP RS		5.7
Varity_R		0.039
gMVP		0.21
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs766766600; hg19: chr10-121431816;