rs196294

chr10-119676443-A-Cchr10-119676443-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004281.4(BAG3):c.910-21A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,611,232 control chromosomes in the GnomAD database, including 407,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37671 hom., cov: 30)
  • Exomes 𝑓: 0.71 (369438 hom.)
• Consequence: BAG3 NM_004281.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.729

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-119676443-A-C is Benign according to our data. Variant chr10-119676443-A-C is described in ClinVar as [Benign]. Clinvar id is 259263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119676443-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4	c.910-21A>C		intron_variant		ENST00000369085.8
BAG3	XM_005270287.2	c.910-24A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.910-21A>C		intron_variant		1	NM_004281.4	P1
BAG3	ENST00000450186.1	c.736-24A>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106489 AN: 151892 Hom.: 37650 Cov.: 30

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.707

GnomAD3 exomes AF: 0.674 AC: 168702 AN: 250360 Hom.: 57747 AF XY: 0.673 AC XY: 91254 AN XY: 135576

Gnomad AFR exome AF: 0.714

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.590

Gnomad FIN exome AF: 0.646

Gnomad NFE exome AF: 0.730

Gnomad OTH exome AF: 0.706

GnomAD4 exome AF: 0.709 AC: 1034366 AN: 1459222 Hom.: 369438 Cov.: 37 AF XY: 0.706 AC XY: 512532 AN XY: 726114

Gnomad4 AFR exome AF: 0.708

Gnomad4 AMR exome AF: 0.631

Gnomad4 ASJ exome AF: 0.787

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.651

Gnomad4 NFE exome AF: 0.730

Gnomad4 OTH exome AF: 0.706

GnomAD4 genome AF: 0.701 AC: 106561 AN: 152010 Hom.: 37671 Cov.: 30 AF XY: 0.694 AC XY: 51583 AN XY: 74284

Gnomad4 AFR AF: 0.713

Gnomad4 AMR AF: 0.692

Gnomad4 ASJ AF: 0.789

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.559

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.728

Gnomad4 OTH AF: 0.704

Alfa AF: 0.727 Hom.: 7466

Bravo AF: 0.707

Asia WGS AF: 0.548 AC: 1909 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Myofibrillar myopathy 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 06, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	5.7
Dann	Benign	0.67

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: rs196294; hg19: chr10-121435955;