dbSNP rs777018751: BAG1:p.Ile292Ser (chr9-33256811-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004323.6(BAG1):c.875T>G(p.Ile292Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I292T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BAG1
NM_004323.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.98

Publications

0 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG1	NM_004323.6 link	c.875T>G	p.Ile292Ser	missense_variant	Exon 5 of 7	ENST00000634734.3	NP_004314.6	Q99933-1
BAG1	NM_001349286.2 link	c.662T>G	p.Ile221Ser	missense_variant	Exon 5 of 7		NP_001336215.1
BAG1	NM_001172415.2 link	c.530T>G	p.Ile177Ser	missense_variant	Exon 5 of 7		NP_001165886.1	Q99933-4
BAG1	NM_001349299.2 link	c.461T>G	p.Ile154Ser	missense_variant	Exon 5 of 7		NP_001336228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG1	ENST00000634734.3 link	c.875T>G	p.Ile292Ser	missense_variant	Exon 5 of 7	1	NM_004323.6	ENSP00000489189.2		Q99933-1J3QTA2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251158

AF XY:

0.00000737

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461080

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111390

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

.;.;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

1.9

.;.;L

PhyloP100

7.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.8

.;D;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

.;D;.

Sift4G

Uncertain

0.011

D;D;.

Polyphen

1.0

.;.;D

Vest4

0.94

MutPred

0.75

Loss of stability (P = 0.0116);.;Loss of stability (P = 0.0116);

MVP

0.91

ClinPred

0.98

GERP RS

5.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.86

gMVP

0.75

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over