10-119651730-C-A

Position:

• chr10-119651730-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004281.4(BAG3):​c.55C>A​(p.Arg19Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.06

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12065908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.55C>A	p.Arg19Ser	missense_variant	1/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.55C>A	p.Arg19Ser	missense_variant	1/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.55C>A	p.Arg19Ser	missense_variant	1/4	1	NM_004281.4	ENSP00000358081.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Jan 15, 2022	This missense variant results in an amino acid substitution of arginine with serine at codon 19 of the BAG3 gene. The variant has an entry in ClinVar (162768) NM_004281.4 (BAG3): c.55C>A (p.Arg19Ser) and has not occurred in population databases. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it benign, and SIFT tolerated, but no functional studies were performed to confirm these predictions. The variant has not occurred in literature associated with disease. Considering that this is a rare variant, whose impact on the protein and association with disease are unknown, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 26, 2013	The Arg19Ser variant in BAG3 has not been reported in individuals with cardiomyo pathy and data from large population studies is insufficient to assess the frequ ency of this variant. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg19Ser variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the cl inical significance of the Arg19Ser variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.57	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.16
Sift	Uncertain	0.018	D
Sift4G	Benign	0.45	T
Polyphen		0.17	B
Vest4		0.12
MutPred		0.18		Gain of glycosylation at R19 (P = 0.0314);
MVP		0.71
MPC		0.44
ClinPred		0.91	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.33

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: rs727502896; hg19: chr10-121411242;