rs606231443
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate
The NM_152296.5(ATP1A3):c.2755_2757del(p.Val919del) variant causes a inframe deletion change. 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. V919V) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
ATP1A3
NM_152296.5 inframe_deletion
NM_152296.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.18
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 7 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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.
PP5
?
Variant 19-41968846-GGAC-G is Pathogenic according to our data. Variant chr19-41968846-GGAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 161147.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968846-GGAC-G is described in Lovd as [Pathogenic]. Variant chr19-41968846-GGAC-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A3 | NM_152296.5 | c.2755_2757del | p.Val919del | inframe_deletion | 20/23 | ENST00000648268.1 | |
ATP1A3 | NM_001256213.2 | c.2788_2790del | p.Val930del | inframe_deletion | 20/23 | ||
ATP1A3 | NM_001256214.2 | c.2794_2796del | p.Val932del | inframe_deletion | 20/23 | ||
ATP1A3 | XM_047438862.1 | c.2665_2667del | p.Val889del | inframe_deletion | 20/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A3 | ENST00000648268.1 | c.2755_2757del | p.Val919del | inframe_deletion | 20/23 | 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
Dystonia 12 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 11, 2022 | This variant, c.2755_2757del, results in the deletion of 1 amino acid(s) of the ATP1A3 protein (p.Val919del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with alternating hemiplegia of childhood (PMID: 22842232; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 161147). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at