10-119651392-G-C

Variant names:

• chr10-119651392-G-C
• rs192502283
• NM_004281.4:c.-284G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1HH

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen
• myofibrillar myopathy 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-tooth disease, axonal, type 2JJ

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• distal hereditary motor neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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: {Benign=1, Uncertain_significance=1, Likely_benign=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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1623 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.-284G>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.-284G>C		5_prime_UTR_variant	Exon 1 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.-284G>C		5_prime_UTR_variant	Exon 1 of 4	1	NM_004281.4	ENSP00000358081.4

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

African (AFR) AF: 0.00212 AC: 9 AN: 4244

American (AMR) AF: 0.0170 AC: 70 AN: 4118

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 85 AN: 5716

East Asian (EAS) AF: 0.00 AC: 0 AN: 13326

South Asian (SAS) AF: 0.00667 AC: 25 AN: 3746

European-Finnish (FIN) AF: 0.00772 AC: 104 AN: 13476

Middle Eastern (MID) AF: 0.0316 AC: 26 AN: 824

European-Non Finnish (NFE) AF: 0.0161 AC: 1686 AN: 104898

Other (OTH) AF: 0.0119 AC: 127 AN: 10680

GnomAD4 genome AF: 0.0107 AC: 1623 AN: 152092 Hom.: 13 Cov.: 33 AF XY: 0.0106 AC XY: 791 AN XY: 74358

African (AFR) AF: 0.00255 AC: 106 AN: 41514

American (AMR) AF: 0.0116 AC: 178 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.00756 AC: 80 AN: 10578

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0157 AC: 1069 AN: 67952

Other (OTH) AF: 0.0180 AC: 38 AN: 2106

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		-0.084
PromoterAI		-0.064	Neutral
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs192502283; hg19: chr10-121410904;