rs376198104

chr10-119670130-G-Achr10-119670130-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004281.4(BAG3):c.460G>A(p.Val154Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V154L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026980013).
• BP6: Variant 10-119670130-G-A is Benign according to our data. Variant chr10-119670130-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 389437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000246 (36/1460552) while in subpopulation SAS AF= 0.000417 (36/86228). AF 95% confidence interval is 0.00031. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4	c.460G>A	p.Val154Met	missense_variant	2/4	ENST00000369085.8
BAG3	XM_005270287.2	c.460G>A	p.Val154Met	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.460G>A	p.Val154Met	missense_variant	2/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1	c.286G>A	p.Val96Met	missense_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000523 AC: 13 AN: 248752 Hom.: 0 AF XY: 0.0000741 AC XY: 10 AN XY: 134900

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: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1460552 Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28 AN XY: 726494

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: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2019

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.060	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.054
Sift	Benign	0.19	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0030	B;.
Vest4		0.14
MutPred		0.29		Gain of helix (P = 0.0078);.;
MVP		0.74
MPC		0.089
ClinPred		0.032	T
GERP RS		3.3
Varity_R		0.052
gMVP		0.21

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: rs376198104; hg19: chr10-121429642;