rs1846841605

Variant names:

• chr10-119651677-T-G
• rs1846841605
• NM_004281.4:c.2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate 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
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 9 codons. Genomic position: 119651700. Lost 0.014 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.2T>G	p.Met1?	start_lost	Exon 1 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.2T>G	p.Met1?	start_lost	Exon 1 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.2T>G	p.Met1?	start_lost	Exon 1 of 4	1	NM_004281.4	ENSP00000358081.4

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

African (AFR) AF: 0.00 AC: 0 AN: 30188

American (AMR) AF: 0.00 AC: 0 AN: 40874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25100

East Asian (EAS) AF: 0.00 AC: 0 AN: 35476

South Asian (SAS) AF: 0.00 AC: 0 AN: 82726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1095966

Other (OTH) AF: 0.00 AC: 0 AN: 58822

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant has not been reported in the literature in individuals with BAG3-related conditions. 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

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BAG3: PM2 -

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
PhyloP100		4.4
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
PromoterAI		-0.057	Neutral
Varity_R		0.95
gMVP		0.52
Mutation Taster		=50/150	disease causing

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

Other links and lift over

dbSNP: rs1846841605; hg19: chr10-121411189;