rs1555866028

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_152296.5(ATP1A3):c.250C>T(p.Arg84Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATP1A3
NM_152296.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.81

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A3. . Gene score misZ: 6.3327 (greater than the threshold 3.09). Trascript score misZ: 9.1232 (greater than threshold 3.09). The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. GenCC has associacion of the gene with 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5 link	c.250C>T	p.Arg84Trp	missense_variant	4/23	ENST00000648268.1	NP_689509.1	P13637-1Q53ES0
ATP1A3	NM_001256214.2 link	c.289C>T	p.Arg97Trp	missense_variant	4/23		NP_001243143.1	P13637-3Q53ES0
ATP1A3	NM_001256213.2 link	c.283C>T	p.Arg95Trp	missense_variant	4/23		NP_001243142.1	P13637-2Q53ES0
ATP1A3	XM_047438862.1 link	c.160C>T	p.Arg54Trp	missense_variant	4/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1 link	c.250C>T	p.Arg84Trp	missense_variant	4/23		NM_152296.5	ENSP00000498113.1		P13637-1
ENSG00000285505	ENST00000644613.1 link	n.250C>T		non_coding_transcript_exon_variant	4/25			ENSP00000494711.1		A0A2R8YEY8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;D;T;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.6

M;M;.;.;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.3

.;D;.;D;D;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;D;.;D;D;.

Sift4G

Pathogenic

0.0010

.;D;D;D;D;.

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.62, 0.62

MutPred

0.54

Gain of catalytic residue at W79 (P = 0.0629);Gain of catalytic residue at W79 (P = 0.0629);.;.;.;.;

MVP

0.84

MPC

2.6

ClinPred

1.0

GERP RS

4.3

Varity_R

0.61

gMVP

0.90

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over