19-41967744-C-G

Position:

• chr19-41967744-C-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_152296.5(ATP1A3):​c.2839G>C​(p.Gly947Arg) 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.90

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.

• PS1: Transcript NM_152296.5 (ATP1A3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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 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). GenCC has associacion of 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, 0.975
• PP5: Variant 19-41967744-C-G is Pathogenic according to our data. Variant chr19-41967744-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 139579.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41967744-C-G is described in Lovd as [Pathogenic]. Variant chr19-41967744-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.2839G>C	p.Gly947Arg	missense_variant	21/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2878G>C	p.Gly960Arg	missense_variant	21/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2872G>C	p.Gly958Arg	missense_variant	21/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2749G>C	p.Gly917Arg	missense_variant	21/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2839G>C	p.Gly947Arg	missense_variant	21/23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.2839G>C		non_coding_transcript_exon_variant	21/25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 12 Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 16, 2021	This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 947 of the ATP1A3 protein (p.Gly947Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has been reported to affect ATP1A3 protein function (PMID: 24631656). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly947 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This missense change has been observed in individual(s) with alternating hemiplegia of childhood (PMID: 22842232). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 139579). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Alternating hemiplegia of childhood 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2014

- -

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	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H;.;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.3	.;D;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D
Polyphen		0.99	D;D;.;.;.
Vest4		0.98, 1.0, 0.98
MutPred		0.87		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);.;.;.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.95
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: rs398122887; hg19: chr19-42471896;