rs144041999

chr10-119669857-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004281.4(BAG3):c.187C>G(p.Pro63Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,614,162 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0820

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041020215).
• BP6: Variant 10-119669857-C-G is Benign according to our data. Variant chr10-119669857-C-G is described in ClinVar as [Benign]. Clinvar id is 178006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119669857-C-G is described in Lovd as [Pathogenic]. Variant chr10-119669857-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00308 (469/152346) while in subpopulation AFR AF= 0.0102 (426/41580). AF 95% confidence interval is 0.00944. There are 2 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4	c.187C>G	p.Pro63Ala	missense_variant	2/4	ENST00000369085.8
BAG3	XM_005270287.2	c.187C>G	p.Pro63Ala	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.187C>G	p.Pro63Ala	missense_variant	2/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1	c.13C>G	p.Pro5Ala	missense_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152228 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00136 AC: 342 AN: 251220 Hom.: 3 AF XY: 0.00120 AC XY: 163 AN XY: 135804

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000523 AC: 765 AN: 1461816 Hom.: 8 Cov.: 32 AF XY: 0.000560 AC XY: 407 AN XY: 727212

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00303

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.00264 AC XY: 197 AN XY: 74494

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.00343

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00157 AC: 191

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Pro63Ala in Exon 02 of BAG3: This variant is not expected to have clinical sig nificance because it has been identified in 1.0% (39/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs144041999). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2017	Variant summary: The BAG3 c.187C>G (p.Pro63Ala) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict benign outcome for this variant. This variant was found in 191/121304 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.011019 (114/10346). This frequency is about 282 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, this variant has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 16, 2023

- -

Atrial fibrillation Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 17, 2019

- -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.53
Dann	Benign	0.71
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.11
Sift	Benign	0.62	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0	B;.
Vest4		0.12
MVP		0.63
MPC		0.068
ClinPred		0.0013	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs144041999; hg19: chr10-121429369;