10-119651677-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004281.4(BAG3):c.2T>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000021 in 1,426,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BAG3 NM_004281.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.39

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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.2T>G	p.Met1?	start_lost	1/4	ENST00000369085.8
BAG3	XM_005270287.2	c.2T>G	p.Met1?	start_lost	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.2T>G	p.Met1?	start_lost	1/4	1	NM_004281.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1426696 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 709516

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: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

BAG3: PM2 -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2019

This sequence change affects the initiator methionine of the BAG3 mRNA. The next in-frame methionine is located at codon 9. This variant is not present in population databases (ExAC 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. This variant has not been reported in the literature in individuals with BAG3-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.070	D
MutationTaster	Benign	0.99	D
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.99		Gain of methylation at M1 (P = 0.0191);
MVP		0.97
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.95
gMVP		0.52

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: rs1846841605; hg19: chr10-121411189;