rs150785666

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_ModerateBS1BS2

The NM_152296.5(ATP1A3):c.1387C>T(p.Arg463Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,614,084 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00066 ( 2 hom. )

Consequence

ATP1A3
NM_152296.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 2.72

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:

ENSG00000285505 (HGNC:):

ENSG00000285505 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in the ATP1A3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 6.3327 (above the threshold of 3.09). Trascript score misZ: 9.1232 (above the threshold of 3.09). GenCC associations: The gene is linked to dystonia 12, alternating hemiplegia of childhood 2, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99, alternating hemiplegia of childhood, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 1, encephalopathy, acute, infection-induced.

BP4

Computational evidence support a benign effect (MetaRNN=0.20119265).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00048 (73/152190) while in subpopulation NFE AF= 0.000808 (55/68038). AF 95% confidence interval is 0.000638. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5 link	c.1387C>T	p.Arg463Cys	missense_variant	Exon 11 of 23	ENST00000648268.1	NP_689509.1	P13637-1Q53ES0
ATP1A3	NM_001256214.2 link	c.1426C>T	p.Arg476Cys	missense_variant	Exon 11 of 23		NP_001243143.1	P13637-3Q53ES0
ATP1A3	NM_001256213.2 link	c.1420C>T	p.Arg474Cys	missense_variant	Exon 11 of 23		NP_001243142.1	P13637-2Q53ES0
ATP1A3	XM_047438862.1 link	c.1297C>T	p.Arg433Cys	missense_variant	Exon 11 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1 link	c.1387C>T	p.Arg463Cys	missense_variant	Exon 11 of 23		NM_152296.5	ENSP00000498113.1		P13637-1
ENSG00000285505	ENST00000644613.1 link	n.1387C>T		non_coding_transcript_exon_variant	Exon 11 of 25			ENSP00000494711.1		A0A2R8YEY8

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000465

AC:

117

AN:

251494

Hom.:

AF XY:

0.000419

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000809

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000664

AC:

971

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000616

AC XY:

448

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000808

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000480

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000622

Hom.:

Bravo

AF:

0.000465

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000535

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dystonia 12

Uncertain:1Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 06, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Jul 10, 2024

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP1A3: PP2, BS2 -

not specified

Uncertain:1

Dec 05, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R463C variant in the ATP1A3 gene has not been previously reported as a pathogenic or benign variant to our knowledge. The R463C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R463C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Alternating hemiplegia of childhood 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases

Benign:1

Aug 30, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

ATP1A3-related disorder

Benign:1

Aug 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;D;T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.56

LIST_S2

Pathogenic

0.99

.;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

1.9

L;L;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.9

.;D;.;D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

.;D;.;D;D

Sift4G

Uncertain

0.010

.;D;D;D;D

Polyphen

0.68

P;P;.;.;.

Vest4

0.40, 0.42, 0.40

MVP

0.91

MPC

2.8

ClinPred

0.11

GERP RS

3.9

Varity_R

0.67

gMVP

0.92

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