rs758641

chr17-3943508-A-G

Variant summary

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

The NM_005173.4(ATP2A3):c.1302T>C(p.Tyr434=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,613,542 control chromosomes in the GnomAD database, including 149,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13315 hom., cov: 31)
  • Exomes 𝑓: 0.42 (136068 hom.)
• Consequence: ATP2A3 NM_005173.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.116

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=-0.66).
• BP6: Variant 17-3943508-A-G is Benign according to our data. Variant chr17-3943508-A-G is described in ClinVar as [Benign]. Clinvar id is 3059760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.116 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A3	NM_005173.4	c.1302T>C	p.Tyr434=	synonymous_variant	11/21	ENST00000397041.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A3	ENST00000397041.8	c.1302T>C	p.Tyr434=	synonymous_variant	11/21	1	NM_005173.4	P1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62078 AN: 151730 Hom.: 13298 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.437

GnomAD3 exomes AF: 0.397 AC: 99922 AN: 251406 Hom.: 21404 AF XY: 0.398 AC XY: 54149 AN XY: 135894

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.0793

Gnomad SAS exome AF: 0.320

Gnomad FIN exome AF: 0.328

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.425 AC: 620526 AN: 1461694 Hom.: 136068 Cov.: 67 AF XY: 0.423 AC XY: 307315 AN XY: 727164

Gnomad4 AFR exome AF: 0.376

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.0710

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.334

Gnomad4 NFE exome AF: 0.447

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.409 AC: 62140 AN: 151848 Hom.: 13315 Cov.: 31 AF XY: 0.404 AC XY: 29950 AN XY: 74208

Gnomad4 AFR AF: 0.381

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.0827

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.433

Alfa AF: 0.444 Hom.: 14101

Bravo AF: 0.417

Asia WGS AF: 0.207 AC: 722 AN: 3478

EpiCase AF: 0.464

EpiControl AF: 0.462

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 17, 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	-0.66
Cadd	Benign	1.0
Dann	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs758641; hg19: chr17-3846802; COSMIC: COSV59227357;