rs1057516032

Positions:

• chr19-41970210-GAGTCT-GGA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Moderate

The NM_152296.5(ATP1A3):​c.2512_2516delinsTC​(p.Arg838_Leu839delinsSer) variant causes a protein altering change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R838R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 protein_altering
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.21

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical (size 22) in uniprot entity AT1A3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_152296.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-41970211-AGTCT-GA is Pathogenic according to our data. Variant chr19-41970211-AGTCT-GA is described in ClinVar as [Pathogenic]. Clinvar id is 369662.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.2512_2516delinsTC	p.Arg838_Leu839delinsSer	protein_altering_variant	18/23	ENST00000648268.1
ATP1A3	NM_001256213.2	c.2545_2549delinsTC	p.Arg849_Leu850delinsSer	protein_altering_variant	18/23
ATP1A3	NM_001256214.2	c.2551_2555delinsTC	p.Arg851_Leu852delinsSer	protein_altering_variant	18/23
ATP1A3	XM_047438862.1	c.2422_2426delinsTC	p.Arg808_Leu809delinsSer	protein_altering_variant	18/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2512_2516delinsTC	p.Arg838_Leu839delinsSer	protein_altering_variant	18/23		NM_152296.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Nov 07, 2014

This variant causes a deletion of an arginine at position 849, and a substitution of a leucine for a serine at position 850, p.(Arg849_Ile850delinsSer). The arginine at position 849 is highly conserved and in the transmembrane domain. This deletion is predicted to be disease-causing by in-silico software and is nove. The leucine at position 850 is highly conserved and in the transmembrane domain. Grantham assessment is deleterious due to conservation and amino acid properties. This substitution is predicted to be disease-causing by in-silico software and is novel. The sequencing data indicates this is a complex variant located on the same strand. Parental testing confirmed the variant to be de novo. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057516032; hg19: chr19-42474363;