X-153536245-A-G

Variant names:

• chrX-153536245-A-G
• rs186232930
• NM_001001344.3:c.-3A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001001344.3(ATP2B3):​c.-3A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,187,770 control chromosomes in the GnomAD database, including 1 homozygotes. There are 75 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., 31 hem., cov: 25)
  • Exomes 𝑓: 0.00012 (1 hom. 44 hem.)
• Consequence: ATP2B3 NM_001001344.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.836

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-153536245-A-G is Benign according to our data. Variant chrX-153536245-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3042913.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000882 (100/113322) while in subpopulation AFR AF= 0.00303 (95/31319). AF 95% confidence interval is 0.00254. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 31 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2B3	NM_001001344.3	c.-3A>G		5_prime_UTR_variant	Exon 3 of 22	ENST00000263519.5	NP_001001344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2B3	ENST00000263519	c.-3A>G		5_prime_UTR_variant	Exon 3 of 22	1	NM_001001344.3	ENSP00000263519.4

Frequencies

GnomAD3 genomes AF: 0.000856 AC: 97 AN: 113272 Hom.: 0 Cov.: 25 AF XY: 0.000819 AC XY: 29 AN XY: 35402

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.000252 AC: 35 AN: 139019 Hom.: 0 AF XY: 0.000277 AC XY: 12 AN XY: 43337

Gnomad AFR exome AF: 0.00313

Gnomad AMR exome AF: 0.0000863

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000351

Gnomad OTH exome AF: 0.000271

GnomAD4 exome AF: 0.000117 AC: 126 AN: 1074448 Hom.: 1 Cov.: 31 AF XY: 0.000126 AC XY: 44 AN XY: 350394

Gnomad4 AFR exome AF: 0.00328

Gnomad4 AMR exome AF: 0.0000942

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000289

Gnomad4 OTH exome AF: 0.000243

GnomAD4 genome AF: 0.000882 AC: 100 AN: 113322 Hom.: 0 Cov.: 25 AF XY: 0.000874 AC XY: 31 AN XY: 35462

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.000185

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.000434 Hom.: 2

Bravo AF: 0.000986

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ATP2B3-related disorder Benign:1

Jul 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.49
CADD	Benign	12
DANN	Benign	0.69

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: rs186232930; hg19: chrX-152801703;