chr19-41978303-C-T

Variant names:

• chr19-41978303-C-T
• rs367904817
• NM_152296.5:c.1654G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_152296.5(ATP1A3):​c.1654G>A​(p.Glu552Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. E552Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64
• Publications: 4 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2004497).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	NM_152296.5	MANE Select	c.1654G>A	p.Glu552Lys	missense	Exon 13 of 23	NP_689509.1
	ATP1A3	NM_001256214.2		c.1693G>A	p.Glu565Lys	missense	Exon 13 of 23	NP_001243143.1
	ATP1A3	NM_001256213.2		c.1687G>A	p.Glu563Lys	missense	Exon 13 of 23	NP_001243142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.1654G>A	p.Glu552Lys	missense	Exon 13 of 23	ENSP00000498113.1
	ENSG00000285505	ENST00000644613.1		n.1654G>A		non_coding_transcript_exon	Exon 13 of 25	ENSP00000494711.1
	ATP1A3	ENST00000545399.6	TSL:2	c.1693G>A	p.Glu565Lys	missense	Exon 13 of 23	ENSP00000444688.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235196 AF XY: 0.00000789

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454698 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722972

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 42752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25842

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 85330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108954

Other (OTH) AF: 0.0000332 AC: 2 AN: 60168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 99 Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1654G>Ap.Glu552Lys variant in ATP1A3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu552Lys variant is present with allele frequency of 0.0004% in gnomAD Exomes. The p.Glu552Lys variant has not been submitted to the ClinVar database. Computational evidence Polyphen - Benign, SIFT - Tolerated and MutationTaster -Disease causing predicts conflicting evidence on protein structure and function for this variant. The reference amino acid at this position is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 552 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.23	N
PhyloP100		2.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.34
Sift	Benign	0.41	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.39
MutPred		0.36		Gain of methylation at E552 (P = 0.0145)
MVP		0.81
MPC		1.5
ClinPred		0.19	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.86
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs367904817; hg19: chr19-42482455; COSMIC: COSV57489041;