chr14-103560828-A-G

Position:

• chr14-103560828-A-G

Variant summary

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

The NM_001015048.3(BAG5):​c.337T>C​(p.Tyr113His) 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. 16/21 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)
• Consequence: BAG5 NM_001015048.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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=0.07110605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG5	NM_001015048.3	c.337T>C	p.Tyr113His	missense_variant	2/2	ENST00000299204.6
BAG5	NM_001015049.5	c.337T>C	p.Tyr113His	missense_variant	2/2
BAG5	NM_004873.4	c.337T>C	p.Tyr113His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG5	ENST00000299204.6	c.337T>C	p.Tyr113His	missense_variant	2/2	1	NM_001015048.3	P1
BAG5	ENST00000337322.5	c.337T>C	p.Tyr113His	missense_variant	2/2	1		P1
BAG5	ENST00000445922.2	c.337T>C	p.Tyr113His	missense_variant	2/2	1		P1
	ENST00000556332.1	n.443-939A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Apr 17, 2023

The c.460T>C (p.Y154H) alteration is located in exon 2 (coding exon 2) of the BAG5 gene. This alteration results from a T to C substitution at nucleotide position 460, causing the tyrosine (Y) at amino acid position 154 to be replaced by a histidine (H). 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	0.085
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.088	T;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T;.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.071	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.13	N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.54	T;T;T;.
Polyphen		0.0	B;B;B;.
Vest4		0.072
MutPred		0.31		Loss of catalytic residue at Y113 (P = 0.0048);Loss of catalytic residue at Y113 (P = 0.0048);.;Loss of catalytic residue at Y113 (P = 0.0048);
MVP		0.80
MPC		0.28
ClinPred		0.12	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.28

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: rs911610105; hg19: chr14-104027165;