rs2217342

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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 (★★).

Frequency

Genomes: 𝑓 0.92 ( 64869 hom., cov: 33)

Exomes 𝑓: 0.90 ( 595802 hom. )

Consequence

ATP1A3
NM_152296.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -4.07

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]

ATP1A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
ATP1A3	NM_152296.5 linkuse as main transcript	c.666T>G	p.Thr222=	synonymous_variant	7/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2 linkuse as main transcript	c.705T>G	p.Thr235=	synonymous_variant	7/23		NP_001243143.1
ATP1A3	NM_001256213.2 linkuse as main transcript	c.699T>G	p.Thr233=	synonymous_variant	7/23		NP_001243142.1
ATP1A3	XM_047438862.1 linkuse as main transcript	c.576T>G	p.Thr192=	synonymous_variant	7/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1 linkuse as main transcript	c.666T>G	p.Thr222=	synonymous_variant	7/23		NM_152296.5	ENSP00000498113		P13637-1

Frequencies

GnomAD3 genomes

AF:

0.922

AC:

140238

AN:

152138

Hom.:

64804

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.899

AC XY:

653920

AN XY:

727238

show subpopulations

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.:

AF XY:

0.921

AC XY:

68525

AN XY:

74438

show subpopulations

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 91. Only high quality variants are reported. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	-	- -

Dystonia 12

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Jul 14, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Alternating hemiplegia of childhood 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over