rs186232930

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

ATP2B3 Gene-Disease associations (from GenCC):

• X-linked progressive cerebellar ataxia

  Inheritance: XL, Unknown Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked non progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 31 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001344.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B3	NM_001001344.3	MANE Select	c.-3A>G		5_prime_UTR	Exon 3 of 22	NP_001001344.1	Q16720-1
	ATP2B3	NM_001388362.1		c.-3A>G		5_prime_UTR	Exon 3 of 22	NP_001375291.1
	ATP2B3	NM_001388361.1		c.-3A>G		5_prime_UTR	Exon 2 of 21	NP_001375290.1	Q16720-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B3	ENST00000263519.5	TSL:1 MANE Select	c.-3A>G		5_prime_UTR	Exon 3 of 22	ENSP00000263519.4	Q16720-1
	ATP2B3	ENST00000359149.9	TSL:1	c.-3A>G		5_prime_UTR	Exon 3 of 23	ENSP00000352062.3	Q16720-2
	ATP2B3	ENST00000496610.2	TSL:3	c.-3A>G		5_prime_UTR	Exon 3 of 23	ENSP00000516173.1	A0A994J5M1

Frequencies

GnomAD3 genomes AF: 0.000856 AC: 97 AN: 113272 Hom.: 0 Cov.: 25

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

GnomAD2 exomes AF: 0.000252 AC: 35 AN: 139019 AF XY: 0.000277

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 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

African (AFR) AF: 0.00328 AC: 85 AN: 25889

American (AMR) AF: 0.0000942 AC: 3 AN: 31854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18857

East Asian (EAS) AF: 0.00 AC: 0 AN: 28764

South Asian (SAS) AF: 0.00 AC: 0 AN: 51099

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38428

Middle Eastern (MID) AF: 0.000729 AC: 3 AN: 4113

European-Non Finnish (NFE) AF: 0.0000289 AC: 24 AN: 830257

Other (OTH) AF: 0.000243 AC: 11 AN: 45187

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

African (AFR) AF: 0.00303 AC: 95 AN: 31319

American (AMR) AF: 0.000185 AC: 2 AN: 10811

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3580

South Asian (SAS) AF: 0.00 AC: 0 AN: 2788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6324

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53390

Other (OTH) AF: 0.00129 AC: 2 AN: 1550

Alfa AF: 0.000434 Hom.: 2

Bravo AF: 0.000986

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ATP2B3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		0.84
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs186232930; hg19: chrX-152801703;