rs45606534
Positions:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_152296.5(ATP1A3):c.2487G>A(p.Pro829=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,208 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0075 ( 10 hom., cov: 32)
Exomes 𝑓: 0.011 ( 99 hom. )
Consequence
ATP1A3
NM_152296.5 synonymous
NM_152296.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.25
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
?
Variant 19-41970240-C-T is Benign according to our data. Variant chr19-41970240-C-T is described in ClinVar as [Benign]. Clinvar id is 329404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41970240-C-T is described in Lovd as [Likely_benign]. Variant chr19-41970240-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-2.25 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00746 (1137/152314) while in subpopulation NFE AF= 0.0129 (875/68022). AF 95% confidence interval is 0.0122. There are 10 homozygotes in gnomad4. There are 530 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 1137 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A3 | NM_152296.5 | c.2487G>A | p.Pro829= | synonymous_variant | 18/23 | ENST00000648268.1 | |
ATP1A3 | NM_001256214.2 | c.2526G>A | p.Pro842= | synonymous_variant | 18/23 | ||
ATP1A3 | NM_001256213.2 | c.2520G>A | p.Pro840= | synonymous_variant | 18/23 | ||
ATP1A3 | XM_047438862.1 | c.2397G>A | p.Pro799= | synonymous_variant | 18/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A3 | ENST00000648268.1 | c.2487G>A | p.Pro829= | synonymous_variant | 18/23 | NM_152296.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00747 AC: 1137AN: 152196Hom.: 10 Cov.: 32
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GnomAD3 exomes AF: 0.00731 AC: 1837AN: 251458Hom.: 11 AF XY: 0.00778 AC XY: 1058AN XY: 135910
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GnomAD4 exome AF: 0.0105 AC: 15350AN: 1461894Hom.: 99 Cov.: 34 AF XY: 0.0103 AC XY: 7477AN XY: 727248
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GnomAD4 genome ? AF: 0.00746 AC: 1137AN: 152314Hom.: 10 Cov.: 32 AF XY: 0.00712 AC XY: 530AN XY: 74484
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ClinVar
Significance: Benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ATP1A3: BP4, BP7, BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2019 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 07, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Dystonia 12 Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Alternating hemiplegia of childhood 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;C1868681:Dystonia 12;C3553788:Alternating hemiplegia of childhood 2;C5562018:Developmental and epileptic encephalopathy 99 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 22, 2021 | - - |
Developmental and epileptic encephalopathy 99 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
ATP1A3-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 03, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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