Genetic Variant BAG1:p.Val146Met (chr9-33264239-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004323.6(BAG1):c.436G>A(p.Val146Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V146L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BAG1
NM_004323.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.891

Publications

2 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20660219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG1	NM_004323.6 link	c.436G>A	p.Val146Met	missense_variant	Exon 1 of 7	ENST00000634734.3	NP_004314.6	Q99933-1
BAG1	NM_001349286.2 link	c.223G>A	p.Val75Met	missense_variant	Exon 1 of 7		NP_001336215.1
BAG1	NM_001172415.2 link	c.91G>A	p.Val31Met	missense_variant	Exon 1 of 7		NP_001165886.1	Q99933-4
BAG1	NM_001349299.2 link	c.22G>A	p.Val8Met	missense_variant	Exon 1 of 7		NP_001336228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG1	ENST00000634734.3 link	c.436G>A	p.Val146Met	missense_variant	Exon 1 of 7	1	NM_004323.6	ENSP00000489189.2		Q99933-1J3QTA2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000830

AC:

AN:

241074

AF XY:

0.00000765

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:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456720

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

44210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

85564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110264

Other (OTH)

AF:

0.00

AC:

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000488

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;.;T;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.75

T;T;T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.5

.;.;M;.;.

PhyloP100

0.89

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

.;N;.;N;.

REVEL

Benign

0.17

Sift

Benign

0.060

.;T;.;D;.

Sift4G

Benign

0.066

T;D;.;.;D

Polyphen

0.97

.;.;D;.;.

Vest4

0.52

MutPred

0.36

Loss of catalytic residue at V146 (P = 0.0882);.;Loss of catalytic residue at V146 (P = 0.0882);.;.;

MVP

0.22

ClinPred

0.72

GERP RS

0.29

PromoterAI

0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.57

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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