8-38176942-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004874.4(BAG4):c.73G>A(p.Gly25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,555,586 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G25D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 16 hom. )

Consequence

BAG4
NM_004874.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.15

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:

LSM1 (HGNC:20472): (LSM1 homolog, mRNA degradation associated) This gene encodes a member of the LSm family of RNA-binding proteins. LSm proteins form stable heteromers that bind specifically to the 3'-terminal oligo(U) tract of U6 snRNA and may play a role in pre-mRNA splicing by mediating U4/U6 snRNP formation. Increased expression of this gene may play a role in cellular transformation and the progression of several malignancies including lung cancer, mesothelioma and breast cancer. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Nov 2011]

LSM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006784469).

BP6

Variant 8-38176942-G-A is Benign according to our data. Variant chr8-38176942-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2658541.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG4	NM_004874.4 link	c.73G>A	p.Gly25Ser	missense_variant	Exon 1 of 5	ENST00000287322.5	NP_004865.1	O95429-1
BAG4	NM_001204878.2 link	c.73G>A	p.Gly25Ser	missense_variant	Exon 1 of 4		NP_001191807.1	O95429-2
LSM1	NR_045493.1 link	n.-212C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG4	ENST00000287322.5 link	c.73G>A	p.Gly25Ser	missense_variant	Exon 1 of 5	1	NM_004874.4	ENSP00000287322.4		O95429-1

Frequencies

GnomAD3 genomes

AF:

0.00295

AC:

449

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00378

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00350

AC:

567

AN:

161938

Hom.:

AF XY:

0.00353

AC XY:

304

AN XY:

86098

show subpopulations

Gnomad AFR exome

AF:

0.00121

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00201

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00423

Gnomad OTH exome

AF:

0.00466

GnomAD4 exome

AF:

0.00371

AC:

5203

AN:

1403210

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

2595

AN XY:

692716

show subpopulations

Gnomad4 AFR exome

AF:

0.000848

Gnomad4 AMR exome

AF:

0.00267

Gnomad4 ASJ exome

AF:

0.0128

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00231

Gnomad4 FIN exome

AF:

0.00241

Gnomad4 NFE exome

AF:

0.00390

Gnomad4 OTH exome

AF:

0.00381

GnomAD4 genome

AF:

0.00295

AC:

449

AN:

152376

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

193

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00378

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00405

Hom.:

Bravo

AF:

0.00318

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.00283

AC:

ExAC

AF:

0.00186

AC:

215

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BAG4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

.;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.90

L;L

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.14

N;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.32

T;T

Polyphen

0.85

.;P

Vest4

0.23

MVP

0.84

MPC

0.10

ClinPred

0.13

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.25

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