NM_004281.4:c.322G>C

Variant names:

• chr10-119669992-G-C
• rs730880053
• NM_004281.4:c.322G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004281.4(BAG3):​c.322G>C​(p.Val108Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V108M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05
• Publications: 2 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056402266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.322G>C	p.Val108Leu	missense_variant	Exon 2 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.322G>C	p.Val108Leu	missense_variant	Exon 2 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.322G>C	p.Val108Leu	missense_variant	Exon 2 of 4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.148G>C	p.Val50Leu	missense_variant	Exon 3 of 5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251476 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 108 of the BAG3 protein (p.Val108Leu). This variant is present in population databases (rs730880053, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.91
DEOGEN2	Benign	0.086	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;.
PhyloP100		3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.11
Sift	Benign	0.41	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.010	B;.
Vest4		0.065
MutPred		0.20		Gain of helix (P = 0.0496);.;
MVP		0.63
MPC		0.068
ClinPred		0.089	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.30
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730880053; hg19: chr10-121429504;