rs2217342

chr19-41985364-A-Cchr19-41985364-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152296.5(ATP1A3):c.666T>G(p.Thr222=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 1,614,130 control chromosomes in the GnomAD database, including 660,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T222T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.92 (64869 hom., cov: 33)
  • Exomes 𝑓: 0.90 (595802 hom.)
• Consequence: ATP1A3 NM_152296.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -4.07

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-41985364-A-C is Benign according to our data. Variant chr19-41985364-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 157926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41985364-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.666T>G	p.Thr222=	synonymous_variant	7/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.705T>G	p.Thr235=	synonymous_variant	7/23
ATP1A3	NM_001256213.2	c.699T>G	p.Thr233=	synonymous_variant	7/23
ATP1A3	XM_047438862.1	c.576T>G	p.Thr192=	synonymous_variant	7/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.666T>G	p.Thr222=	synonymous_variant	7/23		NM_152296.5

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140238 AN: 152138 Hom.: 64804 Cov.: 33

Gnomad AFR AF: 0.981

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.887

GnomAD3 exomes AF: 0.890 AC: 223667 AN: 251436 Hom.: 99713 AF XY: 0.885 AC XY: 120310 AN XY: 135892

Gnomad AFR exome AF: 0.985

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.865

Gnomad EAS exome AF: 0.870

Gnomad SAS exome AF: 0.815

Gnomad FIN exome AF: 0.938

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.886

GnomAD4 exome AF: 0.902 AC: 1318948 AN: 1461874 Hom.: 595802 Cov.: 79 AF XY: 0.899 AC XY: 653920 AN XY: 727238

Gnomad4 AFR exome AF: 0.984

Gnomad4 AMR exome AF: 0.858

Gnomad4 ASJ exome AF: 0.863

Gnomad4 EAS exome AF: 0.878

Gnomad4 SAS exome AF: 0.819

Gnomad4 FIN exome AF: 0.939

Gnomad4 NFE exome AF: 0.909

Gnomad4 OTH exome AF: 0.896

GnomAD4 genome AF: 0.922 AC: 140367 AN: 152256 Hom.: 64869 Cov.: 33 AF XY: 0.921 AC XY: 68525 AN XY: 74438

Gnomad4 AFR AF: 0.981

Gnomad4 AMR AF: 0.883

Gnomad4 ASJ AF: 0.863

Gnomad4 EAS AF: 0.875

Gnomad4 SAS AF: 0.822

Gnomad4 FIN AF: 0.942

Gnomad4 NFE AF: 0.907

Gnomad4 OTH AF: 0.889

Alfa AF: 0.900 Hom.: 80805

Bravo AF: 0.920

EpiCase AF: 0.894

EpiControl AF: 0.897

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Dystonia 12 Benign:3

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Alternating hemiplegia of childhood 2 Benign:2

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	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.012
Dann	Benign	0.19

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

Other links and lift over

dbSNP: rs2217342; hg19: chr19-42489516; COSMIC: COSV57488667; COSMIC: COSV57488667;