rs397515382

Variant names:

• chr19-41966938-C-CAGT
• rs397515382
• NM_152296.5:c.3038_3040dupACT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_152296.5(ATP1A3):​c.3038_3040dupACT​(p.Tyr1013dup) variant causes a conservative inframe insertion 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 (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP1A3 NM_152296.5 conservative_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.34
• Publications: 3 publications found

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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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

ENSG00000285505 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• 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.
• PP5: Variant 19-41966938-C-CAGT is Pathogenic according to our data. Variant chr19-41966938-C-CAGT is described in ClinVar as Pathogenic. ClinVar VariationId is 161154.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152296.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	NM_152296.5	MANE Select	c.3038_3040dupACT	p.Tyr1013dup	conservative_inframe_insertion	Exon 23 of 23	NP_689509.1
	ATP1A3	NM_001256214.2		c.3077_3079dupACT	p.Tyr1026dup	conservative_inframe_insertion	Exon 23 of 23	NP_001243143.1
	ATP1A3	NM_001256213.2		c.3071_3073dupACT	p.Tyr1024dup	conservative_inframe_insertion	Exon 23 of 23	NP_001243142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.3038_3040dupACT	p.Tyr1013dup	conservative_inframe_insertion	Exon 23 of 23	ENSP00000498113.1
	ENSG00000285505	ENST00000644613.1		n.3013+308_3013+310dupACT		intron	N/A	ENSP00000494711.1
	ATP1A3	ENST00000545399.6	TSL:2	c.3077_3079dupACT	p.Tyr1026dup	conservative_inframe_insertion	Exon 23 of 23	ENSP00000444688.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Dystonia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=43/57	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397515382; hg19: chr19-42471090;