14-103560942-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001015048.3(BAG5):c.223A>G(p.Thr75Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BAG5 NM_001015048.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22900814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG5	NM_001015048.3	c.223A>G	p.Thr75Ala	missense_variant	2/2	ENST00000299204.6
BAG5	NM_001015049.5	c.223A>G	p.Thr75Ala	missense_variant	2/2
BAG5	NM_004873.4	c.223A>G	p.Thr75Ala	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG5	ENST00000299204.6	c.223A>G	p.Thr75Ala	missense_variant	2/2	1	NM_001015048.3	P1
BAG5	ENST00000337322.5	c.223A>G	p.Thr75Ala	missense_variant	2/2	1		P1
BAG5	ENST00000445922.2	c.223A>G	p.Thr75Ala	missense_variant	2/2	1		P1
	ENST00000556332.1	n.443-825T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 05, 2022

The c.346A>G (p.T116A) alteration is located in exon 2 (coding exon 2) of the BAG5 gene. This alteration results from a A to G substitution at nucleotide position 346, causing the threonine (T) at amino acid position 116 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	0.13
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.050	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.086	T;T;T;T
Sift4G	Benign	0.092	T;T;T;.
Polyphen		0.037	B;B;B;.
Vest4		0.37
MutPred		0.46		Loss of phosphorylation at T75 (P = 0.0444);Loss of phosphorylation at T75 (P = 0.0444);.;Loss of phosphorylation at T75 (P = 0.0444);
MVP		0.93
MPC		0.22
ClinPred		0.78	D
GERP RS		5.8
Varity_R		0.17
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-104027279;