17-3930386-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005173.4(ATP2A3):c.2659G>A(p.Asp887Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,848 control chromosomes in the GnomAD database, including 1,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.060 (892 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (849 hom.)
• Consequence: ATP2A3 NM_005173.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.74

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029634237).
• BP6: Variant 17-3930386-C-T is Benign according to our data. Variant chr17-3930386-C-T is described in ClinVar as [Benign]. Clinvar id is 3057024.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A3	NM_005173.4	c.2659G>A	p.Asp887Asn	missense_variant	18/21	ENST00000397041.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A3	ENST00000397041.8	c.2659G>A	p.Asp887Asn	missense_variant	18/21	1	NM_005173.4	P1

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9171 AN: 152146 Hom.: 893 Cov.: 31

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0158 AC: 3950 AN: 249718 Hom.: 355 AF XY: 0.0113 AC XY: 1529 AN XY: 135400

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000497

Gnomad OTH exome AF: 0.00821

GnomAD4 exome AF: 0.00619 AC: 9049 AN: 1461584 Hom.: 849 Cov.: 33 AF XY: 0.00528 AC XY: 3839 AN XY: 727050

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000336

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0603 AC: 9182 AN: 152264 Hom.: 892 Cov.: 31 AF XY: 0.0571 AC XY: 4253 AN XY: 74460

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0247

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.0384

Alfa AF: 0.0133 Hom.: 279

Bravo AF: 0.0682

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.207 AC: 914

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0194 AC: 2349

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000652

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

Sep 24, 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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D;.;D;D;D
MetaRNN	Benign	0.0030	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L;L;L;L;L
MutationTaster	Benign	0.000039	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D
REVEL	Uncertain	0.35
Sift	Benign	0.16	T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;.;B;B
Vest4		0.34
MPC		0.52
ClinPred		0.019	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.71

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: rs73330907; hg19: chr17-3833680;