17-3935283-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005173.4(ATP2A3):c.2525-6C>G 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 0.00118 in 1,613,082 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: ATP2A3 NM_005173.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01070
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.242

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-3935283-G-C is Benign according to our data. Variant chr17-3935283-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 723633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2A3	NM_005173.4	c.2525-6C>G		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.2525-6C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005173.4	P1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 223 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00110 AC: 276 AN: 249852 Hom.: 1 AF XY: 0.00123 AC XY: 166 AN XY: 135234

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.000337

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00115 AC: 1682 AN: 1460728 Hom.: 2 Cov.: 30 AF XY: 0.00120 AC XY: 870 AN XY: 726668

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.000247

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74498

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00215 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 11, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 17
DS_AL_spliceai		0.21		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs185342975; hg19: chr17-3838577;