NM_004281.4:c.*218G>C

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: Unknown, AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
• myofibrillar myopathy 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	NM_004281.4	MANE Select	c.*218G>C		3_prime_UTR	Exon 4 of 4	NP_004272.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	ENST00000369085.8	TSL:1 MANE Select	c.*218G>C		3_prime_UTR	Exon 4 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.*218G>C		3_prime_UTR	Exon 5 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.*218G>C		3_prime_UTR	Exon 4 of 4	ENSP00000560037.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dilated cardiomyopathy 1HH (1)
-	-	1	Myofibrillar myopathy 6 (1)
-	-	1	Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH (1)

Computational scores

Source: dbNSFP v4.9

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;