chr19-41966960-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_152296.5(ATP1A3):​c.3019G>A​(p.Val1007Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,388 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 (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ATP1A3
NM_152296.5 missense

Scores

8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.94
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A3. . Gene score misZ 6.3327 (greater than the threshold 3.09). Trascript score misZ 9.1232 (greater than threshold 3.09). GenCC has associacion of gene with dystonia 12, alternating hemiplegia of childhood 2, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99, alternating hemiplegia of childhood, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 1, encephalopathy, acute, infection-induced.
BP4
Computational evidence support a benign effect (MetaRNN=0.42156827).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP1A3NM_152296.5 linkuse as main transcriptc.3019G>A p.Val1007Met missense_variant 23/23 ENST00000648268.1
ATP1A3NM_001256214.2 linkuse as main transcriptc.3058G>A p.Val1020Met missense_variant 23/23
ATP1A3NM_001256213.2 linkuse as main transcriptc.3052G>A p.Val1018Met missense_variant 23/23
ATP1A3XM_047438862.1 linkuse as main transcriptc.2929G>A p.Val977Met missense_variant 23/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP1A3ENST00000648268.1 linkuse as main transcriptc.3019G>A p.Val1007Met missense_variant 23/23 NM_152296.5 P13637-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
7.15e-7
AC:
1
AN:
1399388
Hom.:
0
Cov.:
36
AF XY:
0.00000145
AC XY:
1
AN XY:
690196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.27e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dystonia 12 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 23, 2023This variant has not been reported in the literature in individuals affected with ATP1A3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1007 of the ATP1A3 protein (p.Val1007Met). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T;T;T;.;.
Eigen
Benign
0.12
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.94
.;D;D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.42
T;T;T;T;T
MetaSVM
Uncertain
0.71
D
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-0.81
.;N;.;N;N
REVEL
Uncertain
0.48
Sift
Benign
0.060
.;T;.;T;T
Sift4G
Benign
0.15
.;T;T;T;T
Polyphen
0.17
B;B;.;.;.
Vest4
0.44, 0.46, 0.47, 0.49
MutPred
0.26
Gain of disorder (P = 0.0637);Gain of disorder (P = 0.0637);.;.;.;
MVP
0.89
MPC
2.3
ClinPred
0.96
D
GERP RS
3.1
Varity_R
0.079
gMVP
0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42471112; API