10-119651392-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0840

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]

ACMG classification

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 GnomAd at 1624 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1624 AN: 151984 Hom.: 13 Cov.: 33

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.: 16 Cov.: 0 AF XY: 0.0137 AC XY: 1122 AN XY: 81674

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.: 13 Cov.: 33 AF XY: 0.0106 AC XY: 791 AN XY: 74358

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.: 1

Bravo AF: 0.0119

Asia WGS AF: 0.00261 AC: 10 AN: 3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

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	11
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

Other links and lift over

dbSNP: rs192502283; hg19: chr10-121410904;