rs80356532

Positions:

• chr19-41985090-A-G
• chr19-41985090-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_152296.5(ATP1A3):​c.821T>C​(p.Ile274Thr) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I274N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.19

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 12 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 135) in uniprot entity AT1A3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41985090-A-T is described in Lovd as [Pathogenic].
• 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, 0.988
• PP5: Variant 19-41985090-A-G is Pathogenic according to our data. Variant chr19-41985090-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12910.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-41985090-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.821T>C	p.Ile274Thr	missense_variant	8/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.860T>C	p.Ile287Thr	missense_variant	8/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.854T>C	p.Ile285Thr	missense_variant	8/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.731T>C	p.Ile244Thr	missense_variant	8/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.821T>C	p.Ile274Thr	missense_variant	8/23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.821T>C		non_coding_transcript_exon_variant	8/25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dystonia 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 22, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.2	.;D;.;D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;.;D;D;.
Sift4G	Uncertain	0.038	.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.92, 0.92, 0.92
MutPred		0.92		Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);.;.;.;.;
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.92
gMVP		0.99

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: rs80356532; hg19: chr19-42489242;