8-38207528-C-A

Variant names:

• chr8-38207528-C-A
• rs371334530
• NM_004874.4:c.395C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14
• Publications: 0 publications found

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]

ENSG00000285632 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004874.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG4	NM_004874.4	MANE Select	c.395C>A	p.Thr132Lys	missense	Exon 3 of 5	NP_004865.1	O95429-1
	BAG4	NM_001204878.2		c.287C>A	p.Thr96Lys	missense	Exon 2 of 4	NP_001191807.1	O95429-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG4	ENST00000287322.5	TSL:1 MANE Select	c.395C>A	p.Thr132Lys	missense	Exon 3 of 5	ENSP00000287322.4	O95429-1
	BAG4	ENST00000432471.6	TSL:1	c.287C>A	p.Thr96Lys	missense	Exon 2 of 4	ENSP00000393298.2	O95429-2
	BAG4	ENST00000931320.1		c.379-176C>A		intron	N/A	ENSP00000601379.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250076 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459988 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726216

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111374

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.0024	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.14	T
Polyphen		0.61	P
Vest4		0.71
MVP		0.86
MPC		0.40
ClinPred		0.72	D
GERP RS		5.2
PromoterAI		0.011	Neutral
Varity_R		0.43
gMVP		0.44
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs371334530; hg19: chr8-38065046;