rs754387872

Variant names:

• chr10-119676522-G-A
• rs754387872
• NM_004281.4:c.968G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-119676522-G-A
• chr10-119676522-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004281.4(BAG3):​c.968G>A​(p.Ser323Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S323T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.21
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09269279).
• BS2: High AC in GnomAdExome4 at 26 AD,Unknown 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.968G>A	p.Ser323Asn	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.968G>A	p.Ser323Asn	missense	Exon 4 of 4	ENSP00000358081.4	O95817
	BAG3	ENST00000889977.1		c.968G>A	p.Ser323Asn	missense	Exon 5 of 5	ENSP00000560036.1
	BAG3	ENST00000889978.1		c.965G>A	p.Ser322Asn	missense	Exon 4 of 4	ENSP00000560037.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251480 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461878 Hom.: 0 Cov.: 72 AF XY: 0.0000179 AC XY: 13 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.12
Sift	Benign	0.27	T
Sift4G	Benign	0.30	T
Polyphen		0.013	B
Vest4		0.049
MutPred		0.21		Loss of phosphorylation at S323 (P = 0.0113)
MVP		0.82
MPC		0.16
ClinPred		0.10	T
GERP RS		4.9
Varity_R		0.056
gMVP		0.11
Mutation Taster		=93/7	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: rs754387872; hg19: chr10-121436034;