chr14-103560548-C-G

Position:

• chr14-103560548-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001015048.3(BAG5):​c.617G>C​(p.Gly206Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: BAG5 NM_001015048.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

Genes affected

BAG5 (HGNC:941): (BAG cochaperone 5) 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. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000258851 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG5	NM_001015048.3	c.617G>C	p.Gly206Ala	missense_variant	2/2	ENST00000299204.6	NP_001015048.1
BAG5	NM_001015049.5	c.617G>C	p.Gly206Ala	missense_variant	2/2		NP_001015049.2
BAG5	NM_004873.4	c.617G>C	p.Gly206Ala	missense_variant	2/2		NP_004864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG5	ENST00000299204.6	c.617G>C	p.Gly206Ala	missense_variant	2/2	1	NM_001015048.3	ENSP00000299204.4
BAG5	ENST00000337322.5	c.617G>C	p.Gly206Ala	missense_variant	2/2	1		ENSP00000338814.5
BAG5	ENST00000445922.2	c.617G>C	p.Gly206Ala	missense_variant	2/2	1		ENSP00000391713.2
ENSG00000258851	ENST00000556332.1	n.443-1219C>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727222

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.740G>C (p.G247A) alteration is located in exon 2 (coding exon 2) of the BAG5 gene. This alteration results from a G to C substitution at nucleotide position 740, causing the glycine (G) at amino acid position 247 to be replaced by an alanine (A). 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	Benign	0.30
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.1	L;L;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.96	N;N;N;N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.77
MutPred		0.82		Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);
MVP		0.95
MPC		0.84
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.45
gMVP		0.41

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

Other links and lift over

dbSNP: rs2076064695; hg19: chr14-104026885;