rs1135401822

chr19-41975668-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_152296.5(ATP1A3):c.2224G>T(p.Asp742Tyr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D742V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41975667-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1685558.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ATP1A3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 19-41975668-C-A is Pathogenic according to our data. Variant chr19-41975668-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431156.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.2224G>T	p.Asp742Tyr	missense_variant	16/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.2263G>T	p.Asp755Tyr	missense_variant	16/23
ATP1A3	NM_001256213.2	c.2257G>T	p.Asp753Tyr	missense_variant	16/23
ATP1A3	XM_047438862.1	c.2134G>T	p.Asp712Tyr	missense_variant	16/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2224G>T	p.Asp742Tyr	missense_variant	16/23		NM_152296.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Jan 06, 2017

convulsive encephalopathy; severe hypotonia; distal amyotrophy; stereotypies -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D;D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	5.1	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		1.0	D;D;.;.;.
Vest4		0.96, 0.96, 0.96, 0.96
MutPred		0.77		Loss of catalytic residue at D742 (P = 0.073);Loss of catalytic residue at D742 (P = 0.073);.;.;.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.85
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1135401822; hg19: chr19-42479820;