NM_004874.4:c.170C>T

Variant names:

• chr8-38177039-C-T
• rs1311079690
• NM_004874.4:c.170C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004874.4(BAG4):​c.170C>T​(p.Pro57Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BAG4 NM_004874.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.980
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1880163).

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.170C>T	p.Pro57Leu	missense	Exon 1 of 5	NP_004865.1	O95429-1
	BAG4	NM_001204878.2		c.170C>T	p.Pro57Leu	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.170C>T	p.Pro57Leu	missense	Exon 1 of 5	ENSP00000287322.4	O95429-1
	BAG4	ENST00000432471.6	TSL:1	c.170C>T	p.Pro57Leu	missense	Exon 1 of 4	ENSP00000393298.2	O95429-2
	BAG4	ENST00000931320.1		c.170C>T	p.Pro57Leu	missense	Exon 1 of 5	ENSP00000601379.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.88e-7 AC: 1 AN: 1453560 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722512

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 43422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108658

Other (OTH) AF: 0.00 AC: 0 AN: 59982

GnomAD4 genome Cov.: 32

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	0.097
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.98
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.40
Sift	Benign	0.077	T
Sift4G	Benign	0.096	T
Polyphen		0.027	B
Vest4		0.20
MutPred		0.46		Gain of sheet (P = 0.0221)
MVP		0.83
MPC		0.11
ClinPred		0.86	D
GERP RS		3.7
PromoterAI		0.076	Neutral
Varity_R		0.070
gMVP		0.35
Mutation Taster		=92/8	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: rs1311079690; hg19: chr8-38034557;