rs78439745

Variant names:

• chr10-119672645-G-A
• rs78439745
• NM_004281.4:c.898G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004281.4(BAG3):​c.898G>A​(p.Asp300Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000701 in 1,613,544 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D300D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (15 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.39
• Publications: 9 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 (MetaRNN=0.007756412).
• BP6: Variant 10-119672645-G-A is Benign according to our data. Variant chr10-119672645-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000414 (63/152318) while in subpopulation EAS AF = 0.00734 (38/5176). AF 95% confidence interval is 0.0055. There are 1 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 63 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	NM_004281.4	MANE Select	c.898G>A	p.Asp300Asn	missense	Exon 3 of 4	NP_004272.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	ENST00000369085.8	TSL:1 MANE Select	c.898G>A	p.Asp300Asn	missense	Exon 3 of 4	ENSP00000358081.4
	BAG3	ENST00000450186.1	TSL:5	c.724G>A	p.Asp242Asn	missense	Exon 4 of 5	ENSP00000410036.1
	ENSG00000295480	ENST00000730378.1		n.406-1640C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00732

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000857 AC: 214 AN: 249606 AF XY: 0.000806

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00756

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000731 AC: 1068 AN: 1461226 Hom.: 15 Cov.: 32 AF XY: 0.000715 AC XY: 520 AN XY: 726976

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000939 AC: 42 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26134

East Asian (EAS) AF: 0.0210 AC: 833 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52788

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000674 AC: 75 AN: 1111988

Other (OTH) AF: 0.000662 AC: 40 AN: 60392

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74488

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.000450

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	BAG3-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH (1)
-	-	1	Myofibrillar Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.072	T
Polyphen		0.30	B
Vest4		0.28
MVP		0.84
MPC		0.14
ClinPred		0.024	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.23
Mutation Taster		=93/7	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: rs78439745; hg19: chr10-121432157; COSMIC: COSV100958205;