8-38207691-G-T

Variant names:

• chr8-38207691-G-T
• rs372261481
• NM_004874.4:c.558G>T

Variant summary

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

The NM_004874.4(BAG4):​c.558G>T​(p.Trp186Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 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: 0.0000014 (0 hom.)
• Consequence: BAG4 NM_004874.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

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]

ACMG classification

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 rank	MANE	Protein	UniProt
BAG4	NM_004874.4	c.558G>T	p.Trp186Cys	missense_variant	Exon 3 of 5	ENST00000287322.5	NP_004865.1
BAG4	NM_001204878.2	c.450G>T	p.Trp150Cys	missense_variant	Exon 2 of 4		NP_001191807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG4	ENST00000287322.5	c.558G>T	p.Trp186Cys	missense_variant	Exon 3 of 5	1	NM_004874.4	ENSP00000287322.4
BAG4	ENST00000432471.6	c.450G>T	p.Trp150Cys	missense_variant	Exon 2 of 4	1		ENSP00000393298.2
BAG4	ENST00000521311.1	c.99G>T	p.Trp33Cys	missense_variant	Exon 1 of 2	2		ENSP00000430250.1
BAG4	ENST00000521282.1	n.480G>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.558G>T (p.W186C) alteration is located in exon 3 (coding exon 3) of the BAG4 gene. This alteration results from a G to T substitution at nucleotide position 558, causing the tryptophan (W) at amino acid position 186 to be replaced by a cysteine (C). 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.092	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.82
MutPred		0.45		.;Loss of MoRF binding (P = 0.0817);.;
MVP		0.94
MPC		0.65
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs372261481; hg19: chr8-38065209;