rs3858340

Variant names:

• chr10-119676774-C-T
• rs3858340
• NM_004281.4:c.1220C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004281.4(BAG3):​c.1220C>T​(p.Pro407Leu) variant causes a missense change. The variant allele was found at a frequency of 0.101 in 1,614,030 control chromosomes in the GnomAD database, including 9,406 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P407S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1340 hom., cov: 31)
  • Exomes 𝑓: 0.098 (8066 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 4.50
• Publications: 40 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016813278).
• BP6: Variant 10-119676774-C-T is Benign according to our data. Variant chr10-119676774-C-T is described in ClinVar as Benign. ClinVar VariationId is 44776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

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.1220C>T	p.Pro407Leu	missense	Exon 4 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.1220C>T	p.Pro407Leu	missense	Exon 4 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.1220C>T	p.Pro407Leu	missense	Exon 5 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.1217C>T	p.Pro406Leu	missense	Exon 4 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18793 AN: 152078 Hom.: 1335 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.0827

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.118 AC: 29552 AN: 251250 AF XY: 0.111

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.0757

Gnomad EAS exome AF: 0.266

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0984 AC: 143895 AN: 1461834 Hom.: 8066 Cov.: 79 AF XY: 0.0972 AC XY: 70708 AN XY: 727216

African (AFR) AF: 0.166 AC: 5568 AN: 33480

American (AMR) AF: 0.171 AC: 7651 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 2117 AN: 26136

East Asian (EAS) AF: 0.264 AC: 10461 AN: 39698

South Asian (SAS) AF: 0.0814 AC: 7023 AN: 86258

European-Finnish (FIN) AF: 0.106 AC: 5646 AN: 53386

Middle Eastern (MID) AF: 0.0794 AC: 458 AN: 5766

European-Non Finnish (NFE) AF: 0.0886 AC: 98568 AN: 1112000

Other (OTH) AF: 0.106 AC: 6403 AN: 60396

GnomAD4 genome AF: 0.124 AC: 18816 AN: 152196 Hom.: 1340 Cov.: 31 AF XY: 0.124 AC XY: 9240 AN XY: 74408

African (AFR) AF: 0.167 AC: 6947 AN: 41502

American (AMR) AF: 0.151 AC: 2305 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 289 AN: 3472

East Asian (EAS) AF: 0.261 AC: 1353 AN: 5178

South Asian (SAS) AF: 0.0826 AC: 399 AN: 4832

European-Finnish (FIN) AF: 0.108 AC: 1141 AN: 10582

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0878 AC: 5974 AN: 68020

Other (OTH) AF: 0.129 AC: 272 AN: 2114

Alfa AF: 0.104 Hom.: 2076

Bravo AF: 0.131

TwinsUK AF: 0.0779 AC: 289

ALSPAC AF: 0.0898 AC: 346

ESP6500AA AF: 0.170 AC: 751

ESP6500EA AF: 0.0877 AC: 754

ExAC AF: 0.114 AC: 13856

Asia WGS AF: 0.165 AC: 572 AN: 3478

EpiCase AF: 0.0842

EpiControl AF: 0.0835

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Myofibrillar myopathy 6 (3)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1HH (1)
-	-	1	Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.19	B
Vest4		0.030
MPC		0.070
ClinPred		0.045	T
GERP RS		5.7
Varity_R		0.081
gMVP		0.24
Mutation Taster		=98/2	polymorphism (auto)

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: rs3858340; hg19: chr10-121436286; COSMIC: COSV64841635; COSMIC: COSV64841635;