10-119672373-C-T

Variant names:

• chr10-119672373-C-T
• rs121918312
• NM_004281.4:c.626C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004281.4(BAG3):​c.626C>T​(p.Pro209Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P209A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 6.13
• Publications: 103 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: Unknown, AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
• myofibrillar myopathy 6

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

ENSG00000295480 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-119672372-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1369248.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 10-119672373-C-T is Pathogenic according to our data. Variant chr10-119672373-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	NM_004281.4	MANE Select	c.626C>T	p.Pro209Leu	missense	Exon 3 of 4	NP_004272.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAG3	ENST00000369085.8	TSL:1 MANE Select	c.626C>T	p.Pro209Leu	missense	Exon 3 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.626C>T	p.Pro209Leu	missense	Exon 4 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.626C>T	p.Pro209Leu	missense	Exon 3 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000498 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Myofibrillar myopathy 6 (5)
3	-	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH (1)
1	-	-	Peripheral neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.84		Gain of sheet (P = 0.0266)
MVP		0.99
MPC		0.42
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.71
gMVP		0.65
Mutation Taster		=20/80	disease causing (ClinVar)

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: rs121918312; hg19: chr10-121431885; COSMIC: COSV64842767;