rs191645384

chr19-41988144-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152296.5(ATP1A3):c.154-5C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,112 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (31 hom.)
• Consequence: ATP1A3 NM_152296.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01178
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.449

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=-0.77).
• BP6: Variant 19-41988144-G-C is Benign according to our data. Variant chr19-41988144-G-C is described in ClinVar as [Benign]. Clinvar id is 281502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41988144-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00225 (343/152240) while in subpopulation SAS AF= 0.0137 (66/4832). AF 95% confidence interval is 0.011. There are 2 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.154-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000648268.1
ATP1A3	NM_001256213.2	c.187-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ATP1A3	NM_001256214.2	c.193-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ATP1A3	XM_047438862.1	c.64-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.154-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_152296.5

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 340 AN: 152122 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00345 AC: 866 AN: 250822 Hom.: 5 AF XY: 0.00423 AC XY: 574 AN XY: 135660

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00363 AC: 5301 AN: 1461872 Hom.: 31 Cov.: 33 AF XY: 0.00401 AC XY: 2919 AN XY: 727236

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152240 Hom.: 2 Cov.: 31 AF XY: 0.00231 AC XY: 172 AN XY: 74442

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00277 Hom.: 1

Bravo AF: 0.00186

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00320

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ATP1A3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dystonia 12 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Dec 05, 2021	- -

Alternating hemiplegia of childhood 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 19, 2015

- -

Developmental and epileptic encephalopathy 99 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	13
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.10		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: rs191645384; hg19: chr19-42492296;