NM_004281.4:c.910-21A>C

Variant names:

• chr10-119676443-A-C
• rs196294
• NM_004281.4:c.910-21A>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.910-21A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,611,232 control chromosomes in the GnomAD database, including 407,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37671 hom., cov: 30)
  • Exomes 𝑓: 0.71 (369438 hom.)
• Consequence: BAG3 NM_004281.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.729
• Publications: 11 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=-0.92).
• BP6: Variant 10-119676443-A-C is Benign according to our data. Variant chr10-119676443-A-C is described in ClinVar as Benign. ClinVar VariationId is 259263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.723 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	NM_004281.4	MANE Select	c.910-21A>C		intron	N/A	NP_004272.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	ENST00000369085.8	TSL:1 MANE Select	c.910-21A>C		intron	N/A	ENSP00000358081.4
	BAG3	ENST00000450186.1	TSL:5	c.736-24A>C		intron	N/A	ENSP00000410036.1
	ENSG00000295480	ENST00000730378.1		n.405+465T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106489 AN: 151892 Hom.: 37650 Cov.: 30

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.707

GnomAD2 exomes AF: 0.674 AC: 168702 AN: 250360 AF XY: 0.673

Gnomad AFR exome AF: 0.714

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.646

Gnomad NFE exome AF: 0.730

Gnomad OTH exome AF: 0.706

GnomAD4 exome AF: 0.709 AC: 1034366 AN: 1459222 Hom.: 369438 Cov.: 37 AF XY: 0.706 AC XY: 512532 AN XY: 726114

African (AFR) AF: 0.708 AC: 23659 AN: 33420

American (AMR) AF: 0.631 AC: 28227 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 20561 AN: 26120

East Asian (EAS) AF: 0.477 AC: 18944 AN: 39684

South Asian (SAS) AF: 0.594 AC: 51214 AN: 86174

European-Finnish (FIN) AF: 0.651 AC: 34670 AN: 53256

Middle Eastern (MID) AF: 0.755 AC: 4351 AN: 5764

European-Non Finnish (NFE) AF: 0.730 AC: 810163 AN: 1109780

Other (OTH) AF: 0.706 AC: 42577 AN: 60310

GnomAD4 genome AF: 0.701 AC: 106561 AN: 152010 Hom.: 37671 Cov.: 30 AF XY: 0.694 AC XY: 51583 AN XY: 74284

African (AFR) AF: 0.713 AC: 29530 AN: 41436

American (AMR) AF: 0.692 AC: 10574 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2739 AN: 3472

East Asian (EAS) AF: 0.491 AC: 2539 AN: 5166

South Asian (SAS) AF: 0.559 AC: 2686 AN: 4802

European-Finnish (FIN) AF: 0.644 AC: 6793 AN: 10552

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.728 AC: 49500 AN: 67986

Other (OTH) AF: 0.704 AC: 1484 AN: 2108

Alfa AF: 0.724 Hom.: 12949

Bravo AF: 0.707

Asia WGS AF: 0.548 AC: 1909 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	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	-0.92
CADD	Benign	5.7
DANN	Benign	0.67
PhyloP100		-0.73
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: rs196294; hg19: chr10-121435955; COSMIC: COSV107458258;