8-38177057-T-A

Variant names:

• chr8-38177057-T-A
• NM_004874.4:c.188T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004874.4(BAG4):​c.188T>A​(p.Leu63Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAG4 NM_004874.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049350232).

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.188T>A	p.Leu63Gln	missense	Exon 1 of 5	NP_004865.1	O95429-1
	BAG4	NM_001204878.2		c.188T>A	p.Leu63Gln	missense	Exon 1 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.188T>A	p.Leu63Gln	missense	Exon 1 of 5	ENSP00000287322.4	O95429-1
	BAG4	ENST00000432471.6	TSL:1	c.188T>A	p.Leu63Gln	missense	Exon 1 of 4	ENSP00000393298.2	O95429-2
	BAG4	ENST00000931320.1		c.188T>A	p.Leu63Gln	missense	Exon 1 of 5	ENSP00000601379.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	Benign	0.052
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.15
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.081
MutPred		0.23		Loss of sheet (P = 0.0817)
MVP		0.50
MPC		0.11
ClinPred		0.12	T
GERP RS		2.6
PromoterAI		0.012	Neutral
Varity_R		0.077
gMVP		0.16
Mutation Taster		=91/9	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

hg19: chr8-38034575;