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

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.*39C>G		3_prime_UTR_variant	Exon 23 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.3013+351C>G		intron_variant	Intron 22 of 24			ENSP00000494711.1

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dystonia 12 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;