rs397514619

chrX-153565081-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• 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

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 Pathogenic. Variant got 11 ACMG points.

• 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 id is 39839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B3	NM_001001344.3	c.3320G>A	p.Gly1107Asp	missense_variant	21/22	ENST00000263519.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B3	ENST00000263519.5	c.3320G>A	p.Gly1107Asp	missense_variant	21/22	1	NM_001001344.3	P1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1076121 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 348883

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000619

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ExAC AF: 0.00000845 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2021

The c.3320G>A (p.G1107D) alteration is located in coding exon 19 of the ATP2B3 gene. This alteration results from a G to A substitution at nucleotide position 3320, causing the glycine (G) at amino acid position 1107 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD), the ATP2B3 c.3320G>A alteration was observed in 0.0014% (2/139053) of total alleles studied, with a frequency of 0.0087% (2/23071) in the Latino/Admixed American subpopulation; however this variant was flagged as a low confidence call. No hemizygotes were observed. This alteration has been observed to co-segregate with disease in an X-linked recessive fashion in 2 unrelated families in which affected males presented with childhood ataxia and various other movement abnormalities (Bertini, 2000; Feyma, 2016; Zanni, 2012) The p.G1107 amino acid is conserved in most available vertebrate species. 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). The p.G1107D alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

X-linked progressive cerebellar ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2012

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2017

The G1107D variant in the ATP2B3 gene has been reported previously as a hemizygous in an uncle and his nephew with spinocerebellar ataxia-1 (Zanni et al., 2012). 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). The G1107D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G1107D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G1107D variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

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;.;.;.;D
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;.;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.48
MutPred		0.78		Loss of sheet (P = 0.1158);.;.;Loss of sheet (P = 0.1158);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514619; hg19: chrX-152830539;