rs8946

Variant names:

• chr10-119677500-G-C
• rs8946
• NM_004281.4:c.*218G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004281.4(BAG3):​c.*218G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 674,268 control chromosomes in the GnomAD database, including 46,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (10280 hom., cov: 32)
  • Exomes 𝑓: 0.36 (35836 hom.)
• Consequence: BAG3 NM_004281.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.516
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-119677500-G-C is Benign according to our data. Variant chr10-119677500-G-C is described in ClinVar as Benign. ClinVar VariationId is 298966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.*218G>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.*218G>C		3_prime_UTR_variant	Exon 4 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.*218G>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_004281.4	ENSP00000358081.4

Frequencies

GnomAD3 genomes AF: 0.382 AC: 55659 AN: 145814 Hom.: 10260 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.382

GnomAD4 exome AF: 0.364 AC: 192557 AN: 528338 Hom.: 35836 Cov.: 7 AF XY: 0.363 AC XY: 100605 AN XY: 277516

African (AFR) AF: 0.382 AC: 5355 AN: 14028

American (AMR) AF: 0.341 AC: 7591 AN: 22270

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 4595 AN: 14764

East Asian (EAS) AF: 0.342 AC: 10391 AN: 30402

South Asian (SAS) AF: 0.329 AC: 16208 AN: 49264

European-Finnish (FIN) AF: 0.320 AC: 8929 AN: 27878

Middle Eastern (MID) AF: 0.322 AC: 683 AN: 2124

European-Non Finnish (NFE) AF: 0.379 AC: 128502 AN: 339180

Other (OTH) AF: 0.362 AC: 10303 AN: 28428

GnomAD4 genome AF: 0.382 AC: 55720 AN: 145930 Hom.: 10280 Cov.: 32 AF XY: 0.378 AC XY: 26862 AN XY: 71082

African (AFR) AF: 0.398 AC: 16026 AN: 40278

American (AMR) AF: 0.392 AC: 5487 AN: 14014

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1066 AN: 3236

East Asian (EAS) AF: 0.363 AC: 1830 AN: 5044

South Asian (SAS) AF: 0.332 AC: 1547 AN: 4654

European-Finnish (FIN) AF: 0.336 AC: 3366 AN: 10018

Middle Eastern (MID) AF: 0.296 AC: 81 AN: 274

European-Non Finnish (NFE) AF: 0.386 AC: 25305 AN: 65534

Other (OTH) AF: 0.383 AC: 757 AN: 1974

Alfa AF: 0.375 Hom.: 1299

Bravo AF: 0.373

Asia WGS AF: 0.306 AC: 1064 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26512958)

Myofibrillar myopathy 6 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1HH Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.7
DANN	Benign	0.83
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs8946; hg19: chr10-121437012;