rs606231446

Variant names:

• chr19-41967719-G-T
• rs606231446
• NM_152296.5:c.2864C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP2 PP3_Moderate PP5

The NM_152296.5(ATP1A3):​c.2864C>A​(p.Ala955Asp) 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 Lovd as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_152296.5 (ATP1A3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a transmembrane_region Helical (size 18) in uniprot entity AT1A3_HUMAN there are 6 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, 0.908
• PP5: Variant 19-41967719-G-T is Pathogenic according to our data. Variant chr19-41967719-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.2864C>A	p.Ala955Asp	missense_variant	Exon 21 of 23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2903C>A	p.Ala968Asp	missense_variant	Exon 21 of 23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2897C>A	p.Ala966Asp	missense_variant	Exon 21 of 23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2774C>A	p.Ala925Asp	missense_variant	Exon 21 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2864C>A	p.Ala955Asp	missense_variant	Exon 21 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.2864C>A		non_coding_transcript_exon_variant	Exon 21 of 25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;D;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.6	.;D;.;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Uncertain	0.010	.;D;D;D;D
Polyphen		0.95	P;P;.;.;.
Vest4		0.92, 0.97, 0.93, 0.93
MutPred		0.52		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;
MVP		0.99
MPC		3.2
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.97
gMVP		1.0

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: rs606231446; hg19: chr19-42471871; COSMIC: COSV57491358;