rs542652468

Variant names:

• chr19-41986177-G-A
• rs542652468
• NM_152296.5:c.410C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-41986177-G-A
• chr19-41986177-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.410C>T​(p.Ser137Phe) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000996114: Functional characterization of the p.Ser150Tyr variant demonstrated impaired ATPase activity relative to the reference (PMID 24631656)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S137T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.97
• Publications: 21 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: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000996114: Functional characterization of the p.Ser150Tyr variant demonstrated impaired ATPase activity relative to the reference (PMID 24631656).; SCV001771747: Published functional studies demonstrate a damaging effect; the S137F mutant protein had normal expression but reduced enzyme activity compared with wild type (Heinzen et al., 2012); PMID:24291144
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41986177-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 161121.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 2, dystonia 12, alternating hemiplegia of childhood, encephalopathy, acute, infection-induced, complex neurodevelopmental disorder, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 19-41986177-G-A is Pathogenic according to our data. Variant chr19-41986177-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 161122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.410C>T	p.Ser137Phe	missense	Exon 5 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.449C>T	p.Ser150Phe	missense	Exon 5 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.443C>T	p.Ser148Phe	missense	Exon 5 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.410C>T	p.Ser137Phe	missense	Exon 5 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.410C>T		non_coding_transcript_exon	Exon 5 of 25	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.449C>T	p.Ser150Phe	missense	Exon 5 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000427 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Alternating hemiplegia of childhood 2 (1)
1	-	-	Dystonia 12 (1)
1	-	-	not provided (1)
1	-	-	Seizure;C0678230:Epicanthus;C1836542:Depressed nasal bridge;C3278923:Ventriculomegaly;C4021808:Abnormal earlobe morphology (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		10
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.73		Loss of disorder (P = 0.0301)
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs542652468; hg19: chr19-42490329;