rs141355480

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004281.4(BAG3):c.230C>T(p.Pro77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,614,220 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P77P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.0930

Publications

8 publications found

Variant links:

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

BAG3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013332516).

BP6

Variant 10-119669900-C-T is Benign according to our data. Variant chr10-119669900-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000309 (47/152340) while in subpopulation AMR AF = 0.000523 (8/15308). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 47 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.230C>T	p.Pro77Leu	missense	Exon 2 of 4	NP_004272.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BAG3	ENST00000369085.8	TSL:1 MANE Select	c.230C>T	p.Pro77Leu	missense	Exon 2 of 4	ENSP00000358081.4
BAG3	ENST00000889977.1		c.230C>T	p.Pro77Leu	missense	Exon 3 of 5	ENSP00000560036.1
BAG3	ENST00000889978.1		c.230C>T	p.Pro77Leu	missense	Exon 2 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.000470

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000259

AC:

AN:

251396

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000466

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000313

AC:

458

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

214

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000380

AC:

423

AN:

1112012

Other (OTH)

AF:

0.000281

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000309

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41580

American (AMR)

AF:

0.000523

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000390

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (4)

Cardiomyopathy (2)

Cardiovascular phenotype (1)

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.071

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.63

M_CAP

Benign

0.014

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-2.4

PhyloP100

-0.093

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.72

REVEL

Benign

0.13

Sift

Benign

0.50

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.21

MVP

0.66

MPC

0.071

ClinPred

0.073

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.27

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over