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rs80356537

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_152296.5(ATP1A3):c.2401G>T(p.Asp801Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D801N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP1A3
NM_152296.5 missense

Scores

11
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.81
Variant links:
Genes affected
ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_152296.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-41970405-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, ATP1A3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
Variant 19-41970405-C-A is Pathogenic according to our data. Variant chr19-41970405-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12914.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41970405-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP1A3NM_152296.5 linkuse as main transcriptc.2401G>T p.Asp801Tyr missense_variant 17/23 ENST00000648268.1
ATP1A3NM_001256214.2 linkuse as main transcriptc.2440G>T p.Asp814Tyr missense_variant 17/23
ATP1A3NM_001256213.2 linkuse as main transcriptc.2434G>T p.Asp812Tyr missense_variant 17/23
ATP1A3XM_047438862.1 linkuse as main transcriptc.2311G>T p.Asp771Tyr missense_variant 17/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP1A3ENST00000648268.1 linkuse as main transcriptc.2401G>T p.Asp801Tyr missense_variant 17/23 NM_152296.5 P13637-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dystonia 12 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 16, 2022This missense change has been observed in individual(s) with rapid-onset dystonia-parkinsonism (PMID: 9109901, 15260953). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 801 of the ATP1A3 protein (p.Asp801Tyr). ClinVar contains an entry for this variant (Variation ID: 12914). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp801 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24100174, 26410222). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 27549929, 32653672). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 22, 2004- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
Cadd
Pathogenic
28
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.96
D;D;D;.;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.97
D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H;H;.;.;.
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Pathogenic
0.91
D
Polyphen
1.0
D;D;.;.;.
Vest4
0.98, 0.99, 0.99, 0.99
MutPred
0.65
Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;.;.;
MVP
0.99
MPC
2.8
ClinPred
1.0
D
GERP RS
3.8
Varity_R
0.97
gMVP
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80356537; hg19: chr19-42474557; API