10-119651392-G-C

Position:

chr10-119651392-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004281.4(BAG3):c.-284G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 313,120 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 13 hom., cov: 33)

Exomes 𝑓: 0.013 ( 16 hom. )

Consequence

BAG3
NM_004281.4 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0840

Variant links:

Genes affected

BAG3 (HGNC:939): (BAG cochaperone 3) BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]

BAG3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 10-119651392-G-C is Benign according to our data. Variant chr10-119651392-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298951.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1623/152092) while in subpopulation NFE AF= 0.0157 (1069/67952). AF 95% confidence interval is 0.0149. There are 13 homozygotes in gnomad4. There are 791 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1623 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4 linkuse as main transcript	c.-284G>C		5_prime_UTR_variant	1/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2 linkuse as main transcript	c.-284G>C		5_prime_UTR_variant	1/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8 linkuse as main transcript	c.-284G>C		5_prime_UTR_variant	1/4	1	NM_004281.4	ENSP00000358081	P1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1624

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.0758

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00756

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0182

GnomAD4 exome

AF:

0.0132

AC:

2132

AN:

161028

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1122

AN XY:

81674

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.0170

Gnomad4 ASJ exome

AF:

0.0149

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00667

Gnomad4 FIN exome

AF:

0.00772

Gnomad4 NFE exome

AF:

0.0161

Gnomad4 OTH exome

AF:

0.0119

GnomAD4 genome

AF:

0.0107

AC:

1623

AN:

152092

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

791

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00756

Gnomad4 NFE

AF:

0.0157

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.0119

Asia WGS

AF:

0.00261

AC:

AN:

3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1HH

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Myofibrillar myopathy 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over