Variant 8-38207528-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004874.4(BAG4):c.395C>A(p.Thr132Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,459,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BAG4
NM_004874.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.14

Variant links:

Genes affected

BAG4 (HGNC:940): (BAG cochaperone 4) The protein encoded by this gene is a member of the BAG1-related protein family. BAG1 is an anti-apoptotic protein that functions through interactions with a variety of cell apoptosis and growth related proteins including BCL-2, Raf-protein kinase, steroid hormone receptors, growth factor receptors and members of the heat shock protein 70 kDa family. This protein contains a BAG domain near the C-terminus, which could bind and inhibit the chaperone activity of Hsc70/Hsp70. This protein was found to be associated with the death domain of tumor necrosis factor receptor type 1 (TNF-R1) and death receptor-3 (DR3), and thereby negatively regulates downstream cell death signaling. The regulatory role of this protein in cell death was demonstrated in epithelial cells which undergo apoptosis while integrin mediated matrix contacts are lost. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2011]

BAG4 links:

BAG4 (HGNC:):

BAG4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG4	NM_004874.4 linkuse as main transcript	c.395C>A	p.Thr132Lys	missense_variant	3/5	ENST00000287322.5	NP_004865.1	O95429-1
BAG4	NM_001204878.2 linkuse as main transcript	c.287C>A	p.Thr96Lys	missense_variant	2/4		NP_001191807.1	O95429-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BAG4	ENST00000287322.5 linkuse as main transcript	c.395C>A	p.Thr132Lys	missense_variant	3/5	1	NM_004874.4	ENSP00000287322.4	O95429-1
BAG4	ENST00000432471.6 linkuse as main transcript	c.287C>A	p.Thr96Lys	missense_variant	2/4	1		ENSP00000393298.2	O95429-2
BAG4	ENST00000521282.1 linkuse as main transcript	n.317C>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250076

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135216

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1459988

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726216

show subpopulations

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.395C>A (p.T132K) alteration is located in exon 3 (coding exon 3) of the BAG4 gene. This alteration results from a C to A substitution at nucleotide position 395, causing the threonine (T) at amino acid position 132 to be replaced by a lysine (K). 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

Uncertain

0.40

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.074

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Uncertain

-0.0024

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.61

.;P

Vest4

0.71

MVP

0.86

MPC

0.40

ClinPred

0.72

GERP RS

5.2

Varity_R

0.43

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over