19-41967288-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate
The NM_152296.5(ATP1A3):c.2974G>A(p.Asp992Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D992Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_152296.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP1A3 | NM_152296.5 | c.2974G>A | p.Asp992Asn | missense_variant | 22/23 | ENST00000648268.1 | NP_689509.1 | |
ATP1A3 | NM_001256214.2 | c.3013G>A | p.Asp1005Asn | missense_variant | 22/23 | NP_001243143.1 | ||
ATP1A3 | NM_001256213.2 | c.3007G>A | p.Asp1003Asn | missense_variant | 22/23 | NP_001243142.1 | ||
ATP1A3 | XM_047438862.1 | c.2884G>A | p.Asp962Asn | missense_variant | 22/23 | XP_047294818.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ATP1A3 | ENST00000648268.1 | c.2974G>A | p.Asp992Asn | missense_variant | 22/23 | NM_152296.5 | ENSP00000498113 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249716Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135214
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Dystonia 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Asp992 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been observed in individuals with ATP1A3-related conditions (PMID: 22842232), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 1303306). This missense change has been observed in individual(s) with clinical features of ATP1A3-related conditions (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 992 of the ATP1A3 protein (p.Asp992Asn). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at