rs397514619

Variant names:

• chrX-153565081-G-A
• rs397514619
• NM_001001344.3:c.3320G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_001001344.3(ATP2B3):​c.3320G>A​(p.Gly1107Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,076,121 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000568698: Functional studies expressing the mutated protein in Hela cells showed impaired extrusion of intracellular calcium with prolonged retention of cytoplasmic calcium (Zanni et al., 2012)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: ATP2B3 NM_001001344.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.93
• Publications: 16 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000568698: Functional studies expressing the mutated protein in Hela cells showed impaired extrusion of intracellular calcium with prolonged retention of cytoplasmic calcium (Zanni et al., 2012).; SCV003696211: Functional analysis demonstrated that the p.G1107D alteration interferes with the calmodulin-binding domain (CaM-BD) and it's ability to bind to calmodulin in order to activate the enzyme. In addition, protein with the p.G1107D alteration also has a dysfunctional autoinhibitory mechanism (Calì, 2017). Further in vitro studies observed that overexpressed enzyme with this alteration retains Ca2+ in the cells longer than wildtype suggesting impaired transporting activity (Zanni, 2012).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815
• PP5: Variant X-153565081-G-A is Pathogenic according to our data. Variant chrX-153565081-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 39839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3320G>A	p.Gly1107Asp	missense	Exon 21 of 22	NP_001001344.1	Q16720-1
	ATP2B3	NM_001388362.1		c.3320G>A	p.Gly1107Asp	missense	Exon 21 of 22	NP_001375291.1
	ATP2B3	NM_001388361.1		c.3320G>A	p.Gly1107Asp	missense	Exon 20 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.3320G>A	p.Gly1107Asp	missense	Exon 21 of 22	ENSP00000263519.4	Q16720-1
	ATP2B3	ENST00000359149.9	TSL:1	c.3320G>A	p.Gly1107Asp	missense	Exon 21 of 23	ENSP00000352062.3	Q16720-2
	ATP2B3	ENST00000496610.2	TSL:3	c.3320G>A	p.Gly1107Asp	missense	Exon 21 of 23	ENSP00000516173.1	A0A994J5M1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.0000144 AC: 2 AN: 139053 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

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: 0.00000186 AC: 2 AN: 1076121 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 348883

African (AFR) AF: 0.00 AC: 0 AN: 25860

American (AMR) AF: 0.0000619 AC: 2 AN: 32335

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18923

East Asian (EAS) AF: 0.00 AC: 0 AN: 29033

South Asian (SAS) AF: 0.00 AC: 0 AN: 51133

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3973

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831050

Other (OTH) AF: 0.00 AC: 0 AN: 45218

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000845 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	X-linked progressive cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.78		Loss of sheet (P = 0.1158)
MVP		1.0
MPC		1.7
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.99
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397514619; hg19: chrX-152830539;