rs1555865401

Variant names:

• chr19-41986202-C-T
• rs1555865401
• NM_152296.5:c.385G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.385G>A​(p.Val129Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.14

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]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity AT1A3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 19-41986202-C-T is Pathogenic according to our data. Variant chr19-41986202-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.385G>A	p.Val129Met	missense_variant	Exon 5 of 23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.424G>A	p.Val142Met	missense_variant	Exon 5 of 23		NP_001243143.1
ATP1A3	NM_001256213.2	c.418G>A	p.Val140Met	missense_variant	Exon 5 of 23		NP_001243142.1
ATP1A3	XM_047438862.1	c.295G>A	p.Val99Met	missense_variant	Exon 5 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.385G>A	p.Val129Met	missense_variant	Exon 5 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.385G>A		non_coding_transcript_exon_variant	Exon 5 of 25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:1

Dec 20, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM2, PP2, PP3 -

not provided Pathogenic:1

Sep 02, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously as a de novo variant in a patient with neonatal hypotonia, pervasive developmental disorder, episodes of stiffness when sleeping, severe-injurious behaviors, and childhood-onset schizophrenia (Smedemark-Margulies et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27626066) -

ATP1A3-related disorder Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATP1A3 c.424G>A variant is predicted to result in the amino acid substitution p.Val142Met. This variant is referred to as NM_152296:c.385G>A (p.Val129Met) when reported off of a different transcript. This variant has been reported with de novo occurrence in two individuals, one with childhood-onset schizophrenia (Smedemark-Margulies et al. 2016. PubMed ID: 27626066) and another with an undefined ATP1A3-related phenotype (Vezyroglou et al. 2022. PubMed ID: 36192182). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Juvenile onset psychosis Pathogenic:1

Apr 11, 2016

Gene Discovery Core-Manton Center, Boston Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

de novo -

Dystonia 12 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.0	M;M;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	.;N;.;N;N;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;.;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.67, 0.86, 0.67, 0.67
MutPred		0.66		Loss of catalytic residue at V129 (P = 0.0432);Loss of catalytic residue at V129 (P = 0.0432);.;.;.;.;
MVP		0.85
MPC		2.6
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.79
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555865401; hg19: chr19-42490354;