rs919390

Positions:

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

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong 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. In-silico tool predicts a benign outcome for this variant. 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

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-41966898-G-C is Benign according to our data. Variant chr19-41966898-G-C is described in ClinVar as [Benign]. Clinvar id is 329400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41966898-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.*39C>G		3_prime_UTR_variant	23/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256213.2	c.*39C>G		3_prime_UTR_variant	23/23		NP_001243142.1
ATP1A3	NM_001256214.2	c.*39C>G		3_prime_UTR_variant	23/23		NP_001243143.1
ATP1A3	XM_047438862.1	c.*39C>G		3_prime_UTR_variant	23/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.*39C>G		3_prime_UTR_variant	23/23		NM_152296.5	ENSP00000498113

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

GnomAD3 exomes AF: 0.653 AC: 100268 AN: 153474 Hom.: 33040 AF XY: 0.646 AC XY: 52348 AN XY: 81082

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 SAS exome AF: 0.583

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

Gnomad4 AFR exome AF: 0.779

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.551

Gnomad4 EAS exome AF: 0.815

Gnomad4 SAS exome AF: 0.585

Gnomad4 FIN exome AF: 0.716

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.658

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

Gnomad4 AFR AF: 0.767

Gnomad4 AMR AF: 0.645

Gnomad4 ASJ AF: 0.551

Gnomad4 EAS AF: 0.823

Gnomad4 SAS AF: 0.596

Gnomad4 FIN AF: 0.711

Gnomad4 NFE AF: 0.650

Gnomad4 OTH AF: 0.663

Alfa AF: 0.627 Hom.: 8087

Bravo AF: 0.688

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Dystonia 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 84% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 78. Only high quality variants are reported. -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.4
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs919390; hg19: chr19-42471050;