10-119651590-G-A

Variant names:

• chr10-119651590-G-A
• rs913687992
• NM_004281.4:c.-86G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004281.4(BAG3):​c.-86G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,267,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: BAG3 NM_004281.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.210
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000296 (45/152100) while in subpopulation NFE AF = 0.000544 (37/67960). AF 95% confidence interval is 0.000405. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 45 AD gene.

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.-86G>A		5_prime_UTR	Exon 1 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.-86G>A		5_prime_UTR	Exon 1 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.-86G>A		5_prime_UTR	Exon 2 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.-86G>A		5_prime_UTR	Exon 1 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151990 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000569 AC: 635 AN: 1115064 Hom.: 0 Cov.: 17 AF XY: 0.000542 AC XY: 294 AN XY: 542576

African (AFR) AF: 0.00 AC: 0 AN: 21630

American (AMR) AF: 0.000114 AC: 1 AN: 8806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15288

East Asian (EAS) AF: 0.00 AC: 0 AN: 25970

South Asian (SAS) AF: 0.00 AC: 0 AN: 44196

European-Finnish (FIN) AF: 0.000220 AC: 8 AN: 36380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3334

European-Non Finnish (NFE) AF: 0.000670 AC: 612 AN: 913732

Other (OTH) AF: 0.000306 AC: 14 AN: 45728

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74370

African (AFR) AF: 0.0000723 AC: 3 AN: 41520

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 67960

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000351

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1HH (1)
-	1	-	Myofibrillar myopathy 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		-0.21
PromoterAI		0.062	Neutral
Mutation Taster		=300/0	polymorphism

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: rs913687992; hg19: chr10-121411102;