rs606231444
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_152296.5(ATP1A3):c.2780G>T(p.Cys927Phe) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C927R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
ATP1A3
NM_152296.5 missense
NM_152296.5 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.91
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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr19-41968825-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3730913.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in the ATP1A3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 6.3327 (above the threshold of 3.09). Trascript score misZ: 9.1232 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.938
PP5
Variant 19-41968824-C-A is Pathogenic according to our data. Variant chr19-41968824-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3340419.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP1A3 | NM_152296.5 | c.2780G>T | p.Cys927Phe | missense_variant | Exon 20 of 23 | ENST00000648268.1 | NP_689509.1 | |
| ATP1A3 | NM_001256214.2 | c.2819G>T | p.Cys940Phe | missense_variant | Exon 20 of 23 | NP_001243143.1 | ||
| ATP1A3 | NM_001256213.2 | c.2813G>T | p.Cys938Phe | missense_variant | Exon 20 of 23 | NP_001243142.1 | ||
| ATP1A3 | XM_047438862.1 | c.2690G>T | p.Cys897Phe | missense_variant | Exon 20 of 23 | XP_047294818.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ATP1A3 | ENST00000648268.1 | c.2780G>T | p.Cys927Phe | missense_variant | Exon 20 of 23 | NM_152296.5 | ENSP00000498113.1 | |||
| ENSG00000285505 | ENST00000644613.1 | n.2780G>T | non_coding_transcript_exon_variant | Exon 20 of 25 | ENSP00000494711.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Jan 22, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25447930, 26410222, 27577505, 24431296) -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;.;D;D
Sift4G
Uncertain
.;D;D;D;D
Polyphen
D;D;.;.;.
Vest4
0.94, 0.97, 0.95, 0.95
MutPred
Gain of MoRF binding (P = 0.0821);Gain of MoRF binding (P = 0.0821);.;.;.;
MVP
0.99
MPC
3.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at