rs727502897

Variant names:

• chr10-119651741-GC-G
• rs727502897
• NM_004281.4:c.72delC

Your query was ambiguous. Multiple possible variants found:

• chr10-119651741-GC-G
• chr10-119651741-GC-GCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004281.4(BAG3):​c.72delC​(p.Gly25AspfsTer186) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000415 in 1,447,234 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P24P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BAG3 NM_004281.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.74
• Publications: 2 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 134 pathogenic variants in the truncated region.
• PP5: Variant 10-119651741-GC-G is Pathogenic according to our data. Variant chr10-119651741-GC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.72delC	p.Gly25AspfsTer186	frameshift_variant	Exon 1 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.72delC	p.Gly25AspfsTer186	frameshift_variant	Exon 1 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.72delC	p.Gly25AspfsTer186	frameshift_variant	Exon 1 of 4	1	NM_004281.4	ENSP00000358081.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000212 AC: 5 AN: 236006 AF XY: 0.0000310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1447234 Hom.: 0 Cov.: 31 AF XY: 0.00000833 AC XY: 6 AN XY: 719998

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32176

American (AMR) AF: 0.00 AC: 0 AN: 42924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38516

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105518

Other (OTH) AF: 0.0000335 AC: 2 AN: 59760

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly25Aspfs*186) in the BAG3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAG3 are known to be pathogenic (PMID: 21353195, 25008357). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 162769). For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy Pathogenic:1

Feb 06, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly25fs variant in BAG3 has not been reported in individuals with cardiomyop athy or in large population studies. This frameshift variant is predicted to alt er the protein?s amino acid sequence beginning at position 25 and lead to a prem ature termination codon 186 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Variants in BAG3 are associated with DCM (Arimura 2011, Norton 2011, Villard 2011) and myofibrillar myopathy (Se lcen 2009, Lee 2011) and loss of functions variants have been reported to be dis ease causing (HGMD database). In summary, this variant is likely pathogenic, tho ugh additional studies are required to fully establish its clinical significance . -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=8/192	disease causing (ClinVar)

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: rs727502897; hg19: chr10-121411253; COSMIC: COSV64842091; COSMIC: COSV64842091;