rs201573515
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2
The NM_152296.5(ATP1A3):c.191G>A(p.Arg64Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000644 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R64W) has been classified as Uncertain significance.
Frequency
Consequence
NM_152296.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A3 | NM_152296.5 | c.191G>A | p.Arg64Gln | missense_variant | 4/23 | ENST00000648268.1 | |
ATP1A3 | NM_001256214.2 | c.230G>A | p.Arg77Gln | missense_variant | 4/23 | ||
ATP1A3 | NM_001256213.2 | c.224G>A | p.Arg75Gln | missense_variant | 4/23 | ||
ATP1A3 | XM_047438862.1 | c.101G>A | p.Arg34Gln | missense_variant | 4/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A3 | ENST00000648268.1 | c.191G>A | p.Arg64Gln | missense_variant | 4/23 | NM_152296.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152112Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251162Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135782
GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461886Hom.: 0 Cov.: 33 AF XY: 0.0000564 AC XY: 41AN XY: 727246
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152112Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74304
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy 99 Pathogenic:1
Likely pathogenic, no assertion criteria provided | provider interpretation | Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 19, 2023 | Variant summary: ATP1A3 c.191G>A (p.Arg64Gln) results in a conservative amino acid change located in the Cation-transporting P-type ATPase, N-terminal (IPR004014) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251162 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.191G>A in individuals affected with ATP1A3-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Dystonia 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 64 of the ATP1A3 protein (p.Arg64Gln). This variant is present in population databases (rs201573515, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ATP1A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 468595). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP1A3 protein function. 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2021 | - - |
ATP1A3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at