X-153541366-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001001344.3(ATP2B3):c.216G>A(p.Ala72=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,210,503 control chromosomes in the GnomAD database, including 19 homozygotes. There are 844 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., 146 hem., cov: 24)
  • Exomes 𝑓: 0.0018 (16 hom. 698 hem.)
• Consequence: ATP2B3 NM_001001344.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.05

Genes affected

ATP2B3 (HGNC:816): (ATPase plasma membrane Ca2+ transporting 3) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 3. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-153541366-G-A is Benign according to our data. Variant chrX-153541366-G-A is described in ClinVar as [Benign]. Clinvar id is 787196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (268/112513) while in subpopulation NFE AF= 0.00139 (74/53211). AF 95% confidence interval is 0.00114. There are 3 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B3	NM_001001344.3	c.216G>A	p.Ala72=	synonymous_variant	4/22	ENST00000263519.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B3	ENST00000263519.5	c.216G>A	p.Ala72=	synonymous_variant	4/22	1	NM_001001344.3	P1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 268 AN: 112462 Hom.: 3 Cov.: 24 AF XY: 0.00422 AC XY: 146 AN XY: 34616

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000363

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.00139

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.00328 AC: 601 AN: 183030 Hom.: 5 AF XY: 0.00319 AC XY: 216 AN XY: 67652

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00185 AC: 2026 AN: 1097990 Hom.: 16 Cov.: 32 AF XY: 0.00192 AC XY: 698 AN XY: 363476

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.000905

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00238 AC: 268 AN: 112513 Hom.: 3 Cov.: 24 AF XY: 0.00421 AC XY: 146 AN XY: 34677

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000364

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.00139

Gnomad4 OTH AF: 0.000653

Alfa AF: 0.00254 Hom.: 20

Bravo AF: 0.000510

EpiCase AF: 0.000654

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2018

- -

ATP2B3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 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	-0.85
Cadd	Benign	0.049
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs144855129; hg19: chrX-152806824; COSMIC: COSV54864909;