rs376832654

chr10-119676515-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004281.4(BAG3):c.961C>T(p.Pro321Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

BAG3
NM_004281.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.473

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1333482).

BS2

High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4 linkuse as main transcript	c.961C>T	p.Pro321Ser	missense_variant	4/4	ENST00000369085.8
BAG3	XM_005270287.2 linkuse as main transcript	c.958C>T	p.Pro320Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8 linkuse as main transcript	c.961C>T	p.Pro321Ser	missense_variant	4/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1 linkuse as main transcript	c.784C>T	p.Pro262Ser	missense_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251480

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 02, 2024

Variant summary: BAG3 c.961C>T (p.Pro321Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 1613962 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BAG3 causing Dilated Cardiomyopathy (2.7e-05 vs 3.9e-05), allowing no conclusion about variant significance. c.961C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy without strong evidence of causality (Mazzarotto_2020, McGurk_2023). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the BAG3 protein (p.Pro321Ser). This variant is present in population databases (rs376832654, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 201683). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAG3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2014

p.Pro321Ser (CCA>TCA): c.961 C>T in exon 4 of the BAG3 gene (NM_004281.3). A variant of unknown significance has been identified in the BAG3 gene. The P321S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. P321S was not observed with any significant frequency in 6503 individuals of European and African American descent in the NHLBI Exome Sequencing Project. Missense mutations in nearby residues have not been reported indicating this region of the protein may tolerate change. However, the P321S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Mutations in BAG3 account for approximately 2.5% of familial DCM cases (Hershberger RE and Morales A, 2013). Mutations in BAG3 may also cause myofibrillar myopathy type 6, which is characterized by early-onset, severe, progressive, diffuse muscle weakness associated with cardiomyopathy, severe respiratory insufficiency and spine rigidity (Hershberger RE and Morales A, 2013). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2023

The p.P321S variant (also known as c.961C>T), located in coding exon 4 of the BAG3 gene, results from a C to T substitution at nucleotide position 961. The proline at codon 321 is replaced by serine, an amino acid with similar properties. This variant was reported in one case from a dilated cardiomyopathy (DCM) cohort with limited clinical details provided (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.20

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.018

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

0.99

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

N;D

REVEL

Benign

0.21

Sift

Uncertain

0.018

D;T

Sift4G

Benign

0.18

T;T

Polyphen

0.19

B;.

Vest4

0.084

MVP

0.87

MPC

0.21

ClinPred

0.25

GERP RS

4.9

Varity_R

0.061

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over