17-3928785-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.2863-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,552,320 control chromosomes in the GnomAD database, including 1,704 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.061 (899 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (805 hom.)
• Consequence: ATP2A3 NM_005173.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001748
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.14

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 (BayesDel_noAF=-0.65).
• BP6: Variant 17-3928785-C-T is Benign according to our data. Variant chr17-3928785-C-T is described in ClinVar as [Benign]. Clinvar id is 3056302.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A3	NM_005173.4	c.2863-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000397041.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2A3	ENST00000397041.8	c.2863-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005173.4	P1

Frequencies

GnomAD3 genomes AF: 0.0605 AC: 9185 AN: 151870 Hom.: 900 Cov.: 31

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0393

GnomAD3 exomes AF: 0.0144 AC: 2318 AN: 160988 Hom.: 204 AF XY: 0.0105 AC XY: 897 AN XY: 85480

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000490

Gnomad OTH exome AF: 0.00982

GnomAD4 exome AF: 0.00615 AC: 8614 AN: 1400334 Hom.: 805 Cov.: 31 AF XY: 0.00530 AC XY: 3660 AN XY: 691098

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000390

Gnomad4 FIN exome AF: 0.0000616

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0605 AC: 9196 AN: 151986 Hom.: 899 Cov.: 31 AF XY: 0.0574 AC XY: 4265 AN XY: 74306

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.0245

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000795

Gnomad4 OTH AF: 0.0389

Alfa AF: 0.0294 Hom.: 198

Bravo AF: 0.0687

Asia WGS AF: 0.00924 AC: 33 AN: 3478

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
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.2
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.026
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: rs73328992; hg19: chr17-3832079;