rs3858340

chr10-119676774-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004281.4(BAG3):c.1220C>T(p.Pro407Leu) variant causes a missense change. The variant allele was found at a frequency of 0.101 in 1,614,030 control chromosomes in the GnomAD database, including 9,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P407S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1340 hom., cov: 31)
  • Exomes 𝑓: 0.098 (8066 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.50

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=0.0016813278).
• BP6: Variant 10-119676774-C-T is Benign according to our data. Variant chr10-119676774-C-T is described in ClinVar as [Benign]. Clinvar id is 44776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119676774-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4	c.1220C>T	p.Pro407Leu	missense_variant	4/4	ENST00000369085.8
BAG3	XM_005270287.2	c.1217C>T	p.Pro406Leu	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.1220C>T	p.Pro407Leu	missense_variant	4/4	1	NM_004281.4	P1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18793 AN: 152078 Hom.: 1335 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.0827

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.118 AC: 29552 AN: 251250 Hom.: 2129 AF XY: 0.111 AC XY: 15079 AN XY: 135836

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.0757

Gnomad EAS exome AF: 0.266

Gnomad SAS exome AF: 0.0789

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0984 AC: 143895 AN: 1461834 Hom.: 8066 Cov.: 79 AF XY: 0.0972 AC XY: 70708 AN XY: 727216

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0810

Gnomad4 EAS exome AF: 0.264

Gnomad4 SAS exome AF: 0.0814

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.0886

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.124 AC: 18816 AN: 152196 Hom.: 1340 Cov.: 31 AF XY: 0.124 AC XY: 9240 AN XY: 74408

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0832

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.0826

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0878

Gnomad4 OTH AF: 0.129

Alfa AF: 0.0995 Hom.: 1404

Bravo AF: 0.131

TwinsUK AF: 0.0779 AC: 289

ALSPAC AF: 0.0898 AC: 346

ESP6500AA AF: 0.170 AC: 751

ESP6500EA AF: 0.0877 AC: 754

ExAC AF: 0.114 AC: 13856

Asia WGS AF: 0.165 AC: 572 AN: 3478

EpiCase AF: 0.0842

EpiControl AF: 0.0835

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Pro407Leu in Exon 04 of BAG3: This variant is not expected to have clinical si gnificance because it has been identified in 17.0% (636/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs3858340). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Myofibrillar myopathy 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2017	Variant summary: The BAG3 c.1220C>T (p.Pro407Leu) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict benign outcome for this variant (Mutation Taster not captured due to low reliability index). This variant was found in 13824/121204 control chromosomes (1012 homozygotes) from ExAC at a frequency of 0.1140556, which is approximately 2920 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), thus this variant is a common benign polymorphism. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. In literature, this variant has been reported in one DCM patient who also carried a rare variant p.I206V and was classified as a known polymorphism (Ruppert_2013). Taken together, this variant is classified as benign. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Dilated cardiomyopathy 1HH Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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	0.061
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.23	P
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.19	B
Vest4		0.030
MPC		0.070
ClinPred		0.045	T
GERP RS		5.7
Varity_R		0.081
gMVP		0.24

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: rs3858340; hg19: chr10-121436286; COSMIC: COSV64841635; COSMIC: COSV64841635;