rs782423325

Variant names:

• chr19-41982073-G-A
• rs782423325
• NM_152296.5:c.1027C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3_Moderate

The NM_152296.5(ATP1A3):​c.1027C>T​(p.Arg343Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R343Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.68
• Publications: 2 publications found

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]

ATP1A3 Gene-Disease associations (from GenCC):

• alternating hemiplegia of childhood 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ATP1A3-associated neurological disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy 99

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dystonia 12

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• encephalopathy, acute, infection-induced

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• alternating hemiplegia of childhood

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000285505 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_152296.5
• 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 alternating hemiplegia of childhood 2, developmental and epileptic encephalopathy 99, ATP1A3-associated neurological disorder, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, dystonia 12, alternating hemiplegia of childhood, encephalopathy, acute, infection-induced, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.1027C>T	p.Arg343Trp	missense_variant	Exon 9 of 23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.1066C>T	p.Arg356Trp	missense_variant	Exon 9 of 23		NP_001243143.1
ATP1A3	NM_001256213.2	c.1060C>T	p.Arg354Trp	missense_variant	Exon 9 of 23		NP_001243142.1
ATP1A3	XM_047438862.1	c.937C>T	p.Arg313Trp	missense_variant	Exon 9 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.1027C>T	p.Arg343Trp	missense_variant	Exon 9 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.1027C>T		non_coding_transcript_exon_variant	Exon 9 of 25			ENSP00000494711.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251484 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Apr 02, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29915382) -

Mar 22, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jul 31, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alternating hemiplegia of childhood 2 Uncertain:1

Mar 22, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ATP1A3 related disorder (PMID:29915382). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.736>=0.6, 3CNET: 0.981>=0.75). A missense variant is a common mechanism . The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000080). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1027C>T (p.R343W) alteration is located in exon 9 (coding exon 9) of the ATP1A3 gene. This alteration results from a C to T substitution at nucleotide position 1027, causing the arginine (R) at amino acid position 343 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dystonia 12 Uncertain:1

Jan 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in one or more individuals who were not affected with ATP1A3-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 210382). This variant is present in population databases (rs782423325, ExAC 0.006%). This sequence change replaces arginine with tryptophan at codon 343 of the ATP1A3 protein (p.Arg343Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	.;T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	2.9	M;M;.;.;.
PhyloP100		4.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	.;D;.;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	.;D;.;D;D
Sift4G	Uncertain	0.0030	.;D;D;D;D
Polyphen		0.99	D;D;.;.;.
Vest4		0.55, 0.59, 0.56
MVP		0.73
MPC		2.5
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.77
gMVP		0.96
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs782423325; hg19: chr19-42486225; COSMIC: COSV57488065; COSMIC: COSV57488065;