rs61756328

Variant names:

• chr10-119670133-G-A
• rs61756328
• NM_004281.4:c.463G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004281.4(BAG3):​c.463G>A​(p.Ala155Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,612,584 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A155V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (19 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 2.34
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004027009).
• BP6: Variant 10-119670133-G-A is Benign according to our data. Variant chr10-119670133-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44784.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (365/152280) while in subpopulation NFE AF = 0.00354 (241/68030). AF 95% confidence interval is 0.00318. There are 4 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 365 AD,Unknown 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.463G>A	p.Ala155Thr	missense	Exon 2 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.463G>A	p.Ala155Thr	missense	Exon 2 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.463G>A	p.Ala155Thr	missense	Exon 3 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.463G>A	p.Ala155Thr	missense	Exon 2 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152162 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00291 AC: 719 AN: 247498 AF XY: 0.00290

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00174

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00316 AC: 4619 AN: 1460304 Hom.: 19 Cov.: 34 AF XY: 0.00316 AC XY: 2292 AN XY: 726360

African (AFR) AF: 0.000627 AC: 21 AN: 33476

American (AMR) AF: 0.00139 AC: 62 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 449 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000789 AC: 68 AN: 86232

European-Finnish (FIN) AF: 0.00171 AC: 90 AN: 52706

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5764

European-Non Finnish (NFE) AF: 0.00334 AC: 3708 AN: 1111312

Other (OTH) AF: 0.00335 AC: 202 AN: 60332

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152280 Hom.: 4 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74462

African (AFR) AF: 0.000337 AC: 14 AN: 41528

American (AMR) AF: 0.00137 AC: 21 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00354 AC: 241 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00334 Hom.: 3

Bravo AF: 0.00243

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ExAC AF: 0.00288 AC: 349

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00450

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1HH (1)
-	-	1	Hypertrophic cardiomyopathy (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
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.77
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.071
Sift	Benign	0.80	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.097
MVP		0.71
MPC		0.084
ClinPred		0.0051	T
GERP RS		1.7
Varity_R		0.035
gMVP		0.19
Mutation Taster		=99/1	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: rs61756328; hg19: chr10-121429645;