chr19-41966957-C-T

Variant names:

• chr19-41966957-C-T
• NM_152296.5:c.3022G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_152296.5(ATP1A3):​c.3022G>A​(p.Glu1008Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,386 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 (★). Synonymous variant affecting the same amino acid position (i.e. E1008E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• ATP1A3-associated neurological disorder

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

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

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

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• 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 4 ACMG points.

• 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 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, 0.814

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152296.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	NM_152296.5	MANE Select	c.3022G>A	p.Glu1008Lys	missense	Exon 23 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.3061G>A	p.Glu1021Lys	missense	Exon 23 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.3055G>A	p.Glu1019Lys	missense	Exon 23 of 23	NP_001243142.1	P13637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.3022G>A	p.Glu1008Lys	missense	Exon 23 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.3013+292G>A		intron	N/A	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.3061G>A	p.Glu1021Lys	missense	Exon 23 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399386 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 690198

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35744

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078990

Other (OTH) AF: 0.00 AC: 0 AN: 58018

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.0
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.064	T
Polyphen		0.99	D
Vest4		0.35
MutPred		0.43		Gain of methylation at E1008 (P = 3e-04)
MVP		0.90
MPC		2.7
ClinPred		0.95	D
GERP RS		3.1
Varity_R		0.26
gMVP		0.95
Mutation Taster		=50/50

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

hg19: chr19-42471109;