10-119651382-A-C

Variant names:

• chr10-119651382-A-C
• rs544280047
• NM_004281.4:c.-294A>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.-294A>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 0.00295 in 293,682 control chromosomes in the GnomAD database, including 1 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 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (1 hom.)
• Consequence: BAG3 NM_004281.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.0280
• 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=-0.5).
• BP6: Variant 10-119651382-A-C is Benign according to our data. Variant chr10-119651382-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298947.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00266 (404/152076) while in subpopulation NFE AF = 0.00505 (343/67930). AF 95% confidence interval is 0.00461. There are 0 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 404 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.-294A>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.-294A>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.-294A>C		5_prime_UTR_variant	Exon 1 of 4	1	NM_004281.4	ENSP00000358081.4

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 404 AN: 151970 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000757

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00505

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00327 AC: 463 AN: 141606 Hom.: 1 Cov.: 0 AF XY: 0.00322 AC XY: 231 AN XY: 71818

African (AFR) AF: 0.00102 AC: 4 AN: 3906

American (AMR) AF: 0.00 AC: 0 AN: 3640

Ashkenazi Jewish (ASJ) AF: 0.000397 AC: 2 AN: 5044

East Asian (EAS) AF: 0.00 AC: 0 AN: 11388

South Asian (SAS) AF: 0.00 AC: 0 AN: 3466

European-Finnish (FIN) AF: 0.000613 AC: 7 AN: 11414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 732

European-Non Finnish (NFE) AF: 0.00468 AC: 434 AN: 92660

Other (OTH) AF: 0.00171 AC: 16 AN: 9356

GnomAD4 genome AF: 0.00266 AC: 404 AN: 152076 Hom.: 0 Cov.: 33 AF XY: 0.00235 AC XY: 175 AN XY: 74342

African (AFR) AF: 0.000602 AC: 25 AN: 41528

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000757 AC: 8 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00505 AC: 343 AN: 67930

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00314 Hom.: 0

Bravo AF: 0.00227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BAG3: BS1 -

Myofibrillar myopathy 6 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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.028
PromoterAI		0.13	Neutral
Mutation Taster		=300/0	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: rs544280047; hg19: chr10-121410894;