9-33264284-T-C

Position:

• chr9-33264284-T-C

Variant summary

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

The NM_004323.6(BAG1):​c.391A>G​(p.Ser131Gly) 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 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BAG1 NM_004323.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.370

Genes affected

BAG1 (HGNC:937): (BAG cochaperone 1) The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein encoded by this gene binds to BCL2 and is referred to as BCL2-associated athanogene. It enhances the anti-apoptotic effects of BCL2 and represents a link between growth factor receptors and anti-apoptotic mechanisms. Multiple protein isoforms are encoded by this mRNA through the use of a non-AUG (CUG) initiation codon, and three alternative downstream AUG initiation codons. A related pseudogene has been defined on chromosome X. [provided by RefSeq, Feb 2010]

BAG1 (HGNC:):

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=0.078792214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG1	NM_004323.6	c.391A>G	p.Ser131Gly	missense_variant	1/7	ENST00000634734.3	NP_004314.6
BAG1	NM_001349286.2	c.178A>G	p.Ser60Gly	missense_variant	1/7		NP_001336215.1
BAG1	NM_001172415.2	c.46A>G	p.Ser16Gly	missense_variant	1/7		NP_001165886.1
BAG1	NM_001349299.2	c.-24A>G		5_prime_UTR_variant	1/7		NP_001336228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG1	ENST00000634734.3	c.391A>G	p.Ser131Gly	missense_variant	1/7	1	NM_004323.6	ENSP00000489189.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461744 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727182

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.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.391A>G (p.S131G) alteration is located in exon 1 (coding exon 1) of the BAG1 gene. This alteration results from a A to G substitution at nucleotide position 391, causing the serine (S) at amino acid position 131 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.21	.;.;T;T;.;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.50	T;T;T;T;T;.
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.079	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;L;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	.;N;.;N;.;D
REVEL	Benign	0.037
Sift	Uncertain	0.011	.;D;.;D;.;.
Sift4G	Benign	0.67	T;D;.;.;D;.
Polyphen		0.063	.;.;B;.;.;.
Vest4		0.19
MutPred		0.12		Loss of phosphorylation at S131 (P = 0.0043);.;Loss of phosphorylation at S131 (P = 0.0043);.;.;.;
MVP		0.14
ClinPred		0.082	T
GERP RS		2.1
Varity_R		0.089
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1006995196; hg19: chr9-33264282;