10-119669953-C-G

Position:

• chr10-119669953-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004281.4(BAG3):​c.283C>G​(p.Pro95Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.83

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27124888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.283C>G	p.Pro95Ala	missense_variant	2/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.283C>G	p.Pro95Ala	missense_variant	2/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.283C>G	p.Pro95Ala	missense_variant	2/4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.109C>G	p.Pro37Ala	missense_variant	3/5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2013

Variant classified as Uncertain Significance - Favor Benign. The Pro95Ala varian t in BAG3 has not been reported in individuals with cardiomyopathy or in large p opulation studies. Proline (Pro) at position 95 is conserved in most mammals and evolutionarily distant species, though several mammals (cat, dog, microbat) car ry an alanine (Ala, this variant), suggesting that this change may be tolerated. Additional computational analyses (biochemical amino acid properties, AlignGVGD , PolyPhen2, and SIFT) suggest that this variant may not impact the protein, tho ugh this information is not predictive enough to rule out pathogenicity. In summ ary, the presence of this variant in other mammals suggests that it is more like ly benign, but additional studies are needed to fully assess its clinical signif icance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 162775). This variant has not been reported in the literature in individuals affected with BAG3-related conditions. This variant is present in population databases (rs727502898, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the BAG3 protein (p.Pro95Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.32
Sift	Benign	0.083	T;T
Sift4G	Benign	0.093	T;T
Polyphen		0.33	B;.
Vest4		0.21
MutPred		0.29		Loss of disorder (P = 0.0494);.;
MVP		0.60
MPC		0.11
ClinPred		0.69	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs727502898; hg19: chr10-121429465;