rs919390

Variant names:

• chr19-41966898-G-C
• rs919390
• NM_152296.5:c.*39C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-41966898-G-C
• chr19-41966898-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_152296.5(ATP1A3):​c.*39C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 1,550,440 control chromosomes in the GnomAD database, including 338,434 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36179 hom., cov: 27)
  • Exomes 𝑓: 0.66 (302255 hom.)
• Consequence: ATP1A3 NM_152296.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.92
• Publications: 23 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-41966898-G-C is Benign according to our data. Variant chr19-41966898-G-C is described in ClinVar as Benign. ClinVar VariationId is 329400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

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.*39C>G		3_prime_UTR	Exon 23 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.*39C>G		3_prime_UTR	Exon 23 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.*39C>G		3_prime_UTR	Exon 23 of 23	NP_001243142.1	P13637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.*39C>G		3_prime_UTR	Exon 23 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.3013+351C>G		intron	N/A	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.*39C>G		3_prime_UTR	Exon 23 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 103955 AN: 151274 Hom.: 36156 Cov.: 27

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.660

GnomAD2 exomes AF: 0.653 AC: 100268 AN: 153474 AF XY: 0.646

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.814

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.650

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.656 AC: 917568 AN: 1399050 Hom.: 302255 Cov.: 64 AF XY: 0.652 AC XY: 450212 AN XY: 690022

African (AFR) AF: 0.779 AC: 24617 AN: 31602

American (AMR) AF: 0.615 AC: 21950 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 13863 AN: 25182

East Asian (EAS) AF: 0.815 AC: 29133 AN: 35762

South Asian (SAS) AF: 0.585 AC: 46357 AN: 79242

European-Finnish (FIN) AF: 0.716 AC: 35054 AN: 48966

Middle Eastern (MID) AF: 0.485 AC: 2749 AN: 5666

European-Non Finnish (NFE) AF: 0.654 AC: 705698 AN: 1078906

Other (OTH) AF: 0.658 AC: 38147 AN: 58004

GnomAD4 genome AF: 0.687 AC: 104018 AN: 151390 Hom.: 36179 Cov.: 27 AF XY: 0.685 AC XY: 50677 AN XY: 73962

African (AFR) AF: 0.767 AC: 31545 AN: 41138

American (AMR) AF: 0.645 AC: 9794 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1908 AN: 3464

East Asian (EAS) AF: 0.823 AC: 4220 AN: 5130

South Asian (SAS) AF: 0.596 AC: 2858 AN: 4794

European-Finnish (FIN) AF: 0.711 AC: 7458 AN: 10488

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.650 AC: 44158 AN: 67884

Other (OTH) AF: 0.663 AC: 1397 AN: 2108

Alfa AF: 0.627 Hom.: 8087

Bravo AF: 0.688

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alternating hemiplegia of childhood 2 (2)
-	-	2	Dystonia 12 (2)
-	-	2	not provided (2)
-	-	1	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.4
DANN	Benign	0.88
PhyloP100		2.9
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs919390; hg19: chr19-42471050;