19-41985095-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_152296.5(ATP1A3):​c.816G>A​(p.Thr272=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,872 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 10 hom. )

Consequence

ATP1A3
NM_152296.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -4.02
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 19-41985095-C-T is Benign according to our data. Variant chr19-41985095-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 468607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41985095-C-T is described in Lovd as [Likely_benign]. Variant chr19-41985095-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-4.02 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00146 (223/152342) while in subpopulation NFE AF= 0.00169 (115/68034). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 223 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP1A3NM_152296.5 linkuse as main transcriptc.816G>A p.Thr272= synonymous_variant 8/23 ENST00000648268.1
ATP1A3NM_001256214.2 linkuse as main transcriptc.855G>A p.Thr285= synonymous_variant 8/23
ATP1A3NM_001256213.2 linkuse as main transcriptc.849G>A p.Thr283= synonymous_variant 8/23
ATP1A3XM_047438862.1 linkuse as main transcriptc.726G>A p.Thr242= synonymous_variant 8/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP1A3ENST00000648268.1 linkuse as main transcriptc.816G>A p.Thr272= synonymous_variant 8/23 NM_152296.5 P13637-1

Frequencies

GnomAD3 genomes
AF:
0.00147
AC:
224
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000820
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00131
Gnomad ASJ
AF:
0.0115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00169
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00151
AC:
378
AN:
249866
Hom.:
3
AF XY:
0.00144
AC XY:
194
AN XY:
135162
show subpopulations
Gnomad AFR exome
AF:
0.000498
Gnomad AMR exome
AF:
0.00113
Gnomad ASJ exome
AF:
0.0130
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000852
Gnomad FIN exome
AF:
0.000187
Gnomad NFE exome
AF:
0.00136
Gnomad OTH exome
AF:
0.00262
GnomAD4 exome
AF:
0.00127
AC:
1860
AN:
1461530
Hom.:
10
Cov.:
32
AF XY:
0.00128
AC XY:
930
AN XY:
727032
show subpopulations
Gnomad4 AFR exome
AF:
0.000926
Gnomad4 AMR exome
AF:
0.00103
Gnomad4 ASJ exome
AF:
0.0116
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000928
Gnomad4 FIN exome
AF:
0.000262
Gnomad4 NFE exome
AF:
0.00112
Gnomad4 OTH exome
AF:
0.00192
GnomAD4 genome
AF:
0.00146
AC:
223
AN:
152342
Hom.:
0
Cov.:
32
AF XY:
0.00156
AC XY:
116
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000818
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.0115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00169
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00227
Hom.:
1
Bravo
AF:
0.00141
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00191
EpiControl
AF:
0.00172

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:6
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024ATP1A3: BP4, BP7, BS1 -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMar 05, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 16, 2019- -
Dystonia 12 Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Alternating hemiplegia of childhood 2 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingGenome-Nilou LabDec 05, 2021- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Developmental and epileptic encephalopathy 99 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.32
CADD
Benign
5.9
DANN
Benign
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149898088; hg19: chr19-42489247; API