10-119670121-T-G

Variant names:

• chr10-119670121-T-G
• NM_004281.4:c.451T>G

Variant summary

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

The NM_004281.4(BAG3):​c.451T>G​(p.Cys151Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C151R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.566

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=0.27601337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.451T>G	p.Cys151Gly	missense_variant	Exon 2 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.451T>G	p.Cys151Gly	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.451T>G	p.Cys151Gly	missense_variant	Exon 2 of 4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.277T>G	p.Cys93Gly	missense_variant	Exon 3 of 5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461290 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 726892

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	0.0067	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;D
REVEL	Benign	0.25
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.22	B;.
Vest4		0.45
MutPred		0.15		Gain of catalytic residue at P147 (P = 0.0776);.;
MVP		0.76
MPC		0.30
ClinPred		0.25	T
GERP RS		0.064
Varity_R		0.23
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-121429633;