X-153558109-C-T

Variant names:

• chrX-153558109-C-T
• rs371525355
• NM_001001344.3:c.2434-3C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001344.3(ATP2B3):​c.2434-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,203,095 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: ATP2B3 NM_001001344.3 splice_region, intron
• Scores: Splicing: ADA: 0.002315
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0720
• Publications: 1 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: Unknown, XL Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked non progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

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.2434-3C>T		splice_region intron	N/A	NP_001001344.1	Q16720-1
	ATP2B3	NM_001388362.1		c.2434-3C>T		splice_region intron	N/A	NP_001375291.1
	ATP2B3	NM_001388361.1		c.2434-3C>T		splice_region intron	N/A	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.2434-3C>T		splice_region intron	N/A	ENSP00000263519.4	Q16720-1
	ATP2B3	ENST00000359149.9	TSL:1	c.2434-3C>T		splice_region intron	N/A	ENSP00000352062.3	Q16720-2
	ATP2B3	ENST00000496610.2	TSL:3	c.2434-3C>T		splice_region intron	N/A	ENSP00000516173.1	A0A994J5M1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111246 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000581 AC: 1 AN: 172252 AF XY: 0.00

Gnomad AFR exome AF: 0.0000773

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1091849 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 358271

African (AFR) AF: 0.0000761 AC: 2 AN: 26288

American (AMR) AF: 0.00 AC: 0 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18954

East Asian (EAS) AF: 0.00 AC: 0 AN: 30061

South Asian (SAS) AF: 0.00 AC: 0 AN: 52867

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40257

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838755

Other (OTH) AF: 0.00 AC: 0 AN: 45809

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111246 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33418

African (AFR) AF: 0.0000327 AC: 1 AN: 30556

American (AMR) AF: 0.00 AC: 0 AN: 10536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2633

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6019

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52935

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.9
DANN	Benign	0.84
PhyloP100		0.072

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.050		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: rs371525355; hg19: chrX-152823567;