rs80356535

chr19-41970533-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_152296.5(ATP1A3):c.2273T>G(p.Ile758Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ATP1A3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 19-41970533-A-C is Pathogenic according to our data. Variant chr19-41970533-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12912.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41970533-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.2273T>G	p.Ile758Ser	missense_variant	17/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.2312T>G	p.Ile771Ser	missense_variant	17/23
ATP1A3	NM_001256213.2	c.2306T>G	p.Ile769Ser	missense_variant	17/23
ATP1A3	XM_047438862.1	c.2183T>G	p.Ile728Ser	missense_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2273T>G	p.Ile758Ser	missense_variant	17/23		NM_152296.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 22, 2004

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;T;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
Polyphen		0.96	P;P;.;.;.
Vest4		0.99, 0.99, 0.99
MutPred		0.93		Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);.;.;.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.84
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs80356535; hg19: chr19-42474685;