19-41970211-AGTCT-GA
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM4_SupportingPP3PP5_Moderate
The NM_152296.5(ATP1A3):c.2512_2516delinsTC(p.Arg838_Leu839delinsSer) variant causes a protein altering change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R838R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
ATP1A3
NM_152296.5 protein_altering
NM_152296.5 protein_altering
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.21
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a transmembrane_region Helical (size 22) in uniprot entity AT1A3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_152296.5
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_152296.5. Strenght limited to Supporting due to length of the change: 1aa.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 19-41970211-AGTCT-GA is Pathogenic according to our data. Variant chr19-41970211-AGTCT-GA is described in ClinVar as [Pathogenic]. Clinvar id is 369662.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A3 | NM_152296.5 | c.2512_2516delinsTC | p.Arg838_Leu839delinsSer | protein_altering_variant | 18/23 | ENST00000648268.1 | |
ATP1A3 | NM_001256213.2 | c.2545_2549delinsTC | p.Arg849_Leu850delinsSer | protein_altering_variant | 18/23 | ||
ATP1A3 | NM_001256214.2 | c.2551_2555delinsTC | p.Arg851_Leu852delinsSer | protein_altering_variant | 18/23 | ||
ATP1A3 | XM_047438862.1 | c.2422_2426delinsTC | p.Arg808_Leu809delinsSer | protein_altering_variant | 18/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A3 | ENST00000648268.1 | c.2512_2516delinsTC | p.Arg838_Leu839delinsSer | protein_altering_variant | 18/23 | NM_152296.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Alternating hemiplegia of childhood 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Nov 07, 2014 | This variant causes a deletion of an arginine at position 849, and a substitution of a leucine for a serine at position 850, p.(Arg849_Ile850delinsSer). The arginine at position 849 is highly conserved and in the transmembrane domain. This deletion is predicted to be disease-causing by in-silico software and is nove. The leucine at position 850 is highly conserved and in the transmembrane domain. Grantham assessment is deleterious due to conservation and amino acid properties. This substitution is predicted to be disease-causing by in-silico software and is novel. The sequencing data indicates this is a complex variant located on the same strand. Parental testing confirmed the variant to be de novo. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at