19-41975668-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate

The NM_152296.5(ATP1A3):​c.2224G>T​(p.Asp742Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D742V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP1A3
NM_152296.5 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.88
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.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-41975667-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1685558.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A3. . Gene score misZ 6.3327 (greater than the threshold 3.09). Trascript score misZ 9.1232 (greater than threshold 3.09). GenCC has associacion of gene with dystonia 12, alternating hemiplegia of childhood 2, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99, alternating hemiplegia of childhood, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 1, encephalopathy, acute, infection-induced.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
Variant 19-41975668-C-A is Pathogenic according to our data. Variant chr19-41975668-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431156.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP1A3NM_152296.5 linkuse as main transcriptc.2224G>T p.Asp742Tyr missense_variant 16/23 ENST00000648268.1
ATP1A3NM_001256214.2 linkuse as main transcriptc.2263G>T p.Asp755Tyr missense_variant 16/23
ATP1A3NM_001256213.2 linkuse as main transcriptc.2257G>T p.Asp753Tyr missense_variant 16/23
ATP1A3XM_047438862.1 linkuse as main transcriptc.2134G>T p.Asp712Tyr missense_variant 16/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP1A3ENST00000648268.1 linkuse as main transcriptc.2224G>T p.Asp742Tyr missense_variant 16/23 NM_152296.5 P13637-1

Frequencies

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

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGroupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de ParisJan 06, 2017convulsive encephalopathy; severe hypotonia; distal amyotrophy; stereotypies -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.88
D;D;D;.;.
Eigen
Pathogenic
0.85
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
5.1
H;H;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.6
.;D;.;D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
.;D;.;D;D
Sift4G
Pathogenic
0.0
.;D;D;D;D
Polyphen
1.0
D;D;.;.;.
Vest4
0.96, 0.96, 0.96, 0.96
MutPred
0.77
Loss of catalytic residue at D742 (P = 0.073);Loss of catalytic residue at D742 (P = 0.073);.;.;.;
MVP
0.98
MPC
2.8
ClinPred
1.0
D
GERP RS
4.3
Varity_R
0.85
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs1135401822; hg19: chr19-42479820; API