rs397514506

Positions:

• chr10-119672399-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_004281.4(BAG3):​c.652C>T​(p.Arg218Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R218Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:1
• Conservation: PhyloP100: 1.17

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28359956).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000054 (79/1461884) while in subpopulation EAS AF= 0.00073 (29/39700). AF 95% confidence interval is 0.000522. There are 0 homozygotes in gnomad4_exome. There are 45 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.652C>T	p.Arg218Trp	missense_variant	3/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.652C>T	p.Arg218Trp	missense_variant	3/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.652C>T	p.Arg218Trp	missense_variant	3/4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.478C>T	p.Arg160Trp	missense_variant	4/5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251270 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135878

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 727242

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2024	Reported previously in a patient with DCM and in a patient with muscle disease in the published literature (PMID: 23861362, 29382405); Published functional studies suggest a damaging effect by impairing Z-disc assembly and increasing sensitivity to apoptosis (PMID: 21898660); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29382405, 34426522, 32093037, 30615648, 33658040, 21898660, 23861362, 37216087) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 15, 2023	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 05, 2021	- -

Dilated cardiomyopathy 1HH Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2011

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2023

The p.R218W variant (also known as c.652C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a Japanese proband, diagnosed with dilated cardiomyopathy (DCM) at age 73, who also had three affected siblings. This alteration was shown to disrupt Z-disc assembly in cultured cells; however, the physiological relevance of this finding is uncertain (Arimura T et al. Hum. Mutat., 2011 Dec;32:1481-91). This variant was also detected in a individual with skeletal muscle weakness, and in a stillbirth case where it co-occurred with a variant in a different cardiac-related gene (Wu L et al. Can J Neurol Sci. 2018 05;45(3):262-268; Sahlin E et al. PLoS ONE. 2019 Jan;14(1):e0210017). This variant has also been detected in a cohorts not selected for the presence of disease; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Kars ME et al. Proc Natl Acad Sci U S A. 2021 09;118(36)). This amino acid position is well 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. -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.45
Sift	Benign	0.092	T;T
Sift4G	Benign	0.11	T;T
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.48		Loss of disorder (P = 0.0049);.;
MVP		0.95
MPC		0.42
ClinPred		0.37	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397514506; hg19: chr10-121431911;