rs138078305

chr10-119672392-C-Achr10-119672392-C-Gchr10-119672392-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004281.4(BAG3):c.645C>A(p.Asn215Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N215N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.61

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2392177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4	c.645C>A	p.Asn215Lys	missense_variant	3/4	ENST00000369085.8
BAG3	XM_005270287.2	c.645C>A	p.Asn215Lys	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.645C>A	p.Asn215Lys	missense_variant	3/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1	c.471C>A	p.Asn157Lys	missense_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251246 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135882

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: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 01, 2022

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: 646948). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (Invitae). This variant is present in population databases (rs138078305, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 215 of the BAG3 protein (p.Asn215Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	0.27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	N;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.48	T;T
Polyphen		0.95	P;.
Vest4		0.32
MutPred		0.42		Gain of methylation at N215 (P = 0.0014);.;
MVP		0.84
MPC		0.39
ClinPred		0.44	T
GERP RS		-4.4
Varity_R		0.15
gMVP		0.31

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: rs138078305; hg19: chr10-121431904;