10-119651626-C-T

Variant names:

• chr10-119651626-C-T
• rs527696524
• NM_004281.4:c.-50C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004281.4(BAG3):​c.-50C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,458,480 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: BAG3 NM_004281.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.33
• Publications: 0 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: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen
• myofibrillar myopathy 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-119651626-C-T is Benign according to our data. Variant chr10-119651626-C-T is described in ClinVar as [Benign]. Clinvar id is 201678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00103 (157/151980) while in subpopulation AFR AF = 0.00352 (146/41490). AF 95% confidence interval is 0.00305. There are 2 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 157 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAG3	NM_004281.4	c.-50C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	ENST00000369085.8	NP_004272.2
BAG3	NM_004281.4	c.-50C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.-50C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4		XP_005270344.1
BAG3	XM_005270287.2	c.-50C>T		5_prime_UTR_variant	Exon 1 of 4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.-50C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000369085.8	c.-50C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_004281.4	ENSP00000358081.4

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 151872 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000139 AC: 16 AN: 115222 AF XY: 0.000166

Gnomad AFR exome AF: 0.00299

Gnomad AMR exome AF: 0.000118

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: 0.000399

GnomAD4 exome AF: 0.000103 AC: 134 AN: 1306500 Hom.: 1 Cov.: 30 AF XY: 0.0000933 AC XY: 60 AN XY: 643216

African (AFR) AF: 0.00338 AC: 90 AN: 26624

American (AMR) AF: 0.000224 AC: 6 AN: 26756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21164

East Asian (EAS) AF: 0.00 AC: 0 AN: 28748

South Asian (SAS) AF: 0.0000447 AC: 3 AN: 67178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45290

Middle Eastern (MID) AF: 0.000889 AC: 4 AN: 4500

European-Non Finnish (NFE) AF: 0.00000677 AC: 7 AN: 1033222

Other (OTH) AF: 0.000453 AC: 24 AN: 53018

GnomAD4 genome AF: 0.00103 AC: 157 AN: 151980 Hom.: 2 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74310

African (AFR) AF: 0.00352 AC: 146 AN: 41490

American (AMR) AF: 0.000523 AC: 8 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67902

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.00121

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 02, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.3
DANN	Benign	0.88
PhyloP100		-2.3
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs527696524; hg19: chr10-121411138; COSMIC: COSV100958224; COSMIC: COSV100958224;