chr19-41986177-G-T

Variant names:

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

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.410C>A​(p.Ser137Tyr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S137F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.97

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]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity AT1A3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr19-41986177-G-A is described in Lovd as [Pathogenic].
• 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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 19-41986177-G-T is Pathogenic according to our data. Variant chr19-41986177-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 161121.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-41986177-G-T is described in Lovd as [Pathogenic]. Variant chr19-41986177-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.410C>A	p.Ser137Tyr	missense_variant	Exon 5 of 23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.449C>A	p.Ser150Tyr	missense_variant	Exon 5 of 23		NP_001243143.1
ATP1A3	NM_001256213.2	c.443C>A	p.Ser148Tyr	missense_variant	Exon 5 of 23		NP_001243142.1
ATP1A3	XM_047438862.1	c.320C>A	p.Ser107Tyr	missense_variant	Exon 5 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.410C>A	p.Ser137Tyr	missense_variant	Exon 5 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.410C>A		non_coding_transcript_exon_variant	Exon 5 of 25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 12 Pathogenic:1

Oct 12, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) affected with alternating hemiplegia of childhood (AHC) (PMID: 22842232, 24842602, 24431296). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 161121). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tyrosine at codon 137 of the ATP1A3 protein (p.Ser137Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. This variant has been reported to affect ATP1A3 protein function (PMID: 24631656). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser137 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22842232, 26297560, 26410222). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;D;D;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	2.9	M;M;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.5	.;D;.;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.;D;D;.
Sift4G	Pathogenic	0.0010	.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.82, 0.92, 0.82, 0.83
MutPred		0.68		Loss of disorder (P = 0.0537);Loss of disorder (P = 0.0537);.;.;.;.;
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.91
gMVP		0.97

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: rs542652468; hg19: chr19-42490329;