rs397515577

chr19-41976459-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_152296.5(ATP1A3):c.2051C>T(p.Ser684Phe) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S684Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41976459-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2124880.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ATP1A3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 19-41976459-G-A is Pathogenic according to our data. Variant chr19-41976459-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65759.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41976459-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.2051C>T	p.Ser684Phe	missense_variant	15/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.2090C>T	p.Ser697Phe	missense_variant	15/23
ATP1A3	NM_001256213.2	c.2084C>T	p.Ser695Phe	missense_variant	15/23
ATP1A3	XM_047438862.1	c.1961C>T	p.Ser654Phe	missense_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2051C>T	p.Ser684Phe	missense_variant	15/23		NM_152296.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 12 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2020

This sequence change replaces serine with phenylalanine at codon 684 of the ATP1A3 protein (p.Ser684Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with rapid-onset dystonia-parkinsonism (PMID: 19936820, 24523486, Invitae). ClinVar contains an entry for this variant (Variation ID: 65759). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D;T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
Polyphen		1.0	D;D;.;.;.
Vest4		0.95, 0.96, 0.96, 0.95
MutPred		0.87		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;.;.;
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.65
gMVP		0.97

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

Other links and lift over

dbSNP: rs397515577; hg19: chr19-42480611;