rs35434411

Variant names:

• chr10-119669882-G-A
• rs35434411
• NM_004281.4:c.212G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-119669882-G-A
• chr10-119669882-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004281.4(BAG3):​c.212G>A​(p.Arg71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,614,130 control chromosomes in the GnomAD database, including 697 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (38 hom., cov: 33)
  • Exomes 𝑓: 0.027 (659 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.13
• Publications: 22 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019952059).
• BP6: Variant 10-119669882-G-A is Benign according to our data. Variant chr10-119669882-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0202 (3078/152282) while in subpopulation NFE AF = 0.0317 (2154/68006). AF 95% confidence interval is 0.0306. There are 38 homozygotes in GnomAd4. There are 1456 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3078 AD gene.

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.212G>A	p.Arg71Gln	missense	Exon 2 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.212G>A	p.Arg71Gln	missense	Exon 2 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.212G>A	p.Arg71Gln	missense	Exon 3 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.212G>A	p.Arg71Gln	missense	Exon 2 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3079 AN: 152164 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00538

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0317

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0199 AC: 5005 AN: 251300 AF XY: 0.0200

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00989

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0270 AC: 39502 AN: 1461848 Hom.: 659 Cov.: 32 AF XY: 0.0263 AC XY: 19152 AN XY: 727226

African (AFR) AF: 0.00415 AC: 139 AN: 33480

American (AMR) AF: 0.0110 AC: 493 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00562 AC: 147 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00379 AC: 327 AN: 86256

European-Finnish (FIN) AF: 0.0349 AC: 1864 AN: 53398

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0316 AC: 35189 AN: 1111992

Other (OTH) AF: 0.0219 AC: 1321 AN: 60394

GnomAD4 genome AF: 0.0202 AC: 3078 AN: 152282 Hom.: 38 Cov.: 33 AF XY: 0.0196 AC XY: 1456 AN XY: 74448

African (AFR) AF: 0.00537 AC: 223 AN: 41564

American (AMR) AF: 0.0157 AC: 240 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.0335 AC: 356 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0317 AC: 2154 AN: 68006

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0266 Hom.: 214

Bravo AF: 0.0179

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0326 AC: 280

ExAC AF: 0.0201 AC: 2443

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0269

EpiControl AF: 0.0275

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	2	Myofibrillar myopathy 6 (2)
-	-	1	Cardiomyopathy (1)
-	-	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	0.071
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.072
Sift	Benign	0.49	T
Sift4G	Benign	0.89	T
Polyphen		0.018	B
Vest4		0.068
MPC		0.091
ClinPred		0.0079	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.33
Mutation Taster		=95/5	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: rs35434411; hg19: chr10-121429394;