17-3925408-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000572116.1(ATP2A3):c.399A>G(p.Arg133=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,613,220 control chromosomes in the GnomAD database, including 104,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8348 hom., cov: 31)
  • Exomes 𝑓: 0.36 (95894 hom.)
• Consequence: ATP2A3 ENST00000572116.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.46

Genes affected

ATP2A3 (HGNC:813): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in calcium sequestration associated with muscular excitation and contraction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 17-3925408-T-C is Benign according to our data. Variant chr17-3925408-T-C is described in ClinVar as [Benign]. Clinvar id is 3059152.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A3	NM_005173.4	c.*14A>G		3_prime_UTR_variant	21/21	ENST00000397041.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A3	ENST00000397041.8	c.*14A>G		3_prime_UTR_variant	21/21	1	NM_005173.4	P1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48944 AN: 151776 Hom.: 8333 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.341

GnomAD3 exomes AF: 0.352 AC: 87833 AN: 249482 Hom.: 16034 AF XY: 0.350 AC XY: 47234 AN XY: 134974

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.282

Gnomad SAS exome AF: 0.288

Gnomad FIN exome AF: 0.323

Gnomad NFE exome AF: 0.376

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.360 AC: 526316 AN: 1461326 Hom.: 95894 Cov.: 50 AF XY: 0.358 AC XY: 260513 AN XY: 726950

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.323 AC: 49005 AN: 151894 Hom.: 8348 Cov.: 31 AF XY: 0.321 AC XY: 23842 AN XY: 74234

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.402

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.341

Alfa AF: 0.364 Hom.: 15438

Bravo AF: 0.329

Asia WGS AF: 0.266 AC: 925 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ATP2A3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	15
Dann	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs887387; hg19: chr17-3828702; COSMIC: COSV59225720; COSMIC: COSV59225720;