19-41970405-C-G

Position:

• chr19-41970405-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_152296.5(ATP1A3):​c.2401G>C​(p.Asp801His) 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. D801N) 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: 7.81

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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41970405-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ATP1A3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 19-41970405-C-G is Pathogenic according to our data. Variant chr19-41970405-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210383.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.2401G>C	p.Asp801His	missense_variant	17/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.2440G>C	p.Asp814His	missense_variant	17/23
ATP1A3	NM_001256213.2	c.2434G>C	p.Asp812His	missense_variant	17/23
ATP1A3	XM_047438862.1	c.2311G>C	p.Asp771His	missense_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2401G>C	p.Asp801His	missense_variant	17/23		NM_152296.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 07, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
Polyphen		1.0	D;D;.;.;.
Vest4		0.98, 0.98, 0.98
MutPred		0.61		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;.;.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356537; hg19: chr19-42474557;