rs145393807

chr10-119669950-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004281.4(BAG3):c.280A>T(p.Ile94Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000974 in 1,614,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:17
• Conservation: PhyloP100: 5.02

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04835871).
• BP6: Variant 10-119669950-A-T is Benign according to our data. Variant chr10-119669950-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178007.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=4, Uncertain_significance=2}. Variant chr10-119669950-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000788 (120/152328) while in subpopulation NFE AF= 0.00138 (94/68020). AF 95% confidence interval is 0.00116. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAG3	NM_004281.4	c.280A>T	p.Ile94Phe	missense_variant	2/4	ENST00000369085.8
BAG3	XM_005270287.2	c.280A>T	p.Ile94Phe	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAG3	ENST00000369085.8	c.280A>T	p.Ile94Phe	missense_variant	2/4	1	NM_004281.4	P1
BAG3	ENST00000450186.1	c.106A>T	p.Ile36Phe	missense_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000640 AC: 161 AN: 251488 Hom.: 0 AF XY: 0.000596 AC XY: 81 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000994 AC: 1453 AN: 1461894 Hom.: 1 Cov.: 32 AF XY: 0.000979 AC XY: 712 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74490

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.000771

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:10

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BAG3: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 17, 2015	The patient had genetic testing with a comprehensive cardiomyopathy panel. The test included 77 genes associated with various hereditary cardiomyopathies: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3, BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Analysis included both sequencing and array-based comparative genome hybridization to look for duplications and deletions (excluding mitochondrial genes, FKTN, GATAD1) Results showed that a variant was found: -p.Ile94Phe (c.280 A>T in the BAG3 gene. This variant is reviewed in detail below. The lab classifies this variant as a variant of unknown significance. Given a lack of case data, lack of segregation and presence in the general population we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least two unrelated cases of DCM in the literature (not including this patient's family). In one family this variant failed to segregate with disease. Villard E et al., 2011 reported finding this variant in one individual with familial DCM, but failed to segregate in an affected individual and was thereby excluded as a disease causing variant. Norton N et al., 2011 also reported this variant in one individual with DCM but was reported as a variant because of its presence in controls. The Laboratory for Molecular Medicine has seen this in one individual and classifies this as a a variant of uncertain significance. Emory Genetics, the Biesecker Lab classify this as likely benign. In silico analysis with PolyPhen-2 predicts the variant to be damaging (HumVar: 0.975). The Ile at codon 94 is conserved across species, as are neighboring amino acids. Other variants have not been reported in association with disease at this codon (94) and nearby codons. There is substantial variation at codon 94 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 17, 2015). This is a population frequency of 1/682 people in the cohort. 91 of those individuals were European with a frequency of 1/400 caucasian individuals. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2020	This variant is associated with the following publications: (PMID: 21353195, 21459883, 27042682, 27896284, 23861362, 26350513, 26886200, 28798025) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 30, 2023	- -

not specified Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Ile94Phe vari ant in BAG3 has been identified in 0.1% (89/66712) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14 5393807). It has been reported in 2 individuals with DCM, though it reportedly d id not segregate with disease in 1 affected relative (Norton 2011, Villard 2011) . This variant has also been identified by our laboratory in one individual with reduced ejection fraction, hypokinesis and LBBB. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, while the clinical significance of the p.Ile94Phe variant is uncertain, its frequency and lack of segregation with disease suggest s that it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2017	- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

Jul 03, 2019

- -

Myofibrillar myopathy 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.048	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;T
Polyphen		1.0	D;.
Vest4		0.91
MVP		0.95
MPC		0.51
ClinPred		0.16	T
GERP RS		5.4
Varity_R		0.43
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145393807; hg19: chr10-121429462;