chr19-41968824-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_152296.5(ATP1A3):c.2780G>A(p.Cys927Tyr) 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. 13/22 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. C927R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP1A3
NM_152296.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.91

Publications

8 publications found

Variant links:

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

ATP1A3 links:

ENSG00000285505 (HGNC:):

ENSG00000285505 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr19-41968825-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 3730913.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 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, 0.941

PP5

Variant 19-41968824-C-T is Pathogenic according to our data. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41968824-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 3382957.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5 link	c.2780G>A	p.Cys927Tyr	missense_variant	Exon 20 of 23	ENST00000648268.1	NP_689509.1	P13637-1Q53ES0
ATP1A3	NM_001256214.2 link	c.2819G>A	p.Cys940Tyr	missense_variant	Exon 20 of 23		NP_001243143.1	P13637-3Q53ES0
ATP1A3	NM_001256213.2 link	c.2813G>A	p.Cys938Tyr	missense_variant	Exon 20 of 23		NP_001243142.1	P13637-2Q53ES0
ATP1A3	XM_047438862.1 link	c.2690G>A	p.Cys897Tyr	missense_variant	Exon 20 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1 link	c.2780G>A	p.Cys927Tyr	missense_variant	Exon 20 of 23		NM_152296.5	ENSP00000498113.1		P13637-1
ENSG00000285505	ENST00000644613.1 link	n.2780G>A		non_coding_transcript_exon_variant	Exon 20 of 25			ENSP00000494711.1		A0A2R8YEY8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;C1868681:Dystonia 12;C3553788:Alternating hemiplegia of childhood 2;C5562018:Developmental and epileptic encephalopathy 99

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS4_Supporting+PM6_Supporting+PP3+PP4+PM1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;D;D;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;H;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-4.7

.;D;.;D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0060

.;D;.;D;D

Sift4G

Uncertain

0.0060

.;D;D;D;D

Polyphen

0.97

D;D;.;.;.

Vest4

0.95, 0.98, 0.95, 0.95

MutPred

0.74

Loss of methylation at K928 (P = 0.0231);Loss of methylation at K928 (P = 0.0231);.;.;.;

MVP

0.99

MPC

3.4

ClinPred

1.0

GERP RS

3.4

Varity_R

0.95

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over