rs149898088

Positions:

• chr19-41985095-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152296.5(ATP1A3):​c.816G>A​(p.Thr272=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,872 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (10 hom.)
• Consequence: ATP1A3 NM_152296.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -4.02

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-41985095-C-T is Benign according to our data. Variant chr19-41985095-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 468607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41985095-C-T is described in Lovd as [Likely_benign]. Variant chr19-41985095-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00146 (223/152342) while in subpopulation NFE AF= 0.00169 (115/68034). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 223 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.816G>A	p.Thr272=	synonymous_variant	8/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.855G>A	p.Thr285=	synonymous_variant	8/23
ATP1A3	NM_001256213.2	c.849G>A	p.Thr283=	synonymous_variant	8/23
ATP1A3	XM_047438862.1	c.726G>A	p.Thr242=	synonymous_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.816G>A	p.Thr272=	synonymous_variant	8/23		NM_152296.5

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00151 AC: 378 AN: 249866 Hom.: 3 AF XY: 0.00144 AC XY: 194 AN XY: 135162

Gnomad AFR exome AF: 0.000498

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000852

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00127 AC: 1860 AN: 1461530 Hom.: 10 Cov.: 32 AF XY: 0.00128 AC XY: 930 AN XY: 727032

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000928

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74500

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00141

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ATP1A3: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	- -

Dystonia 12 Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
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, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

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	-0.32
CADD	Benign	5.9
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs149898088; hg19: chr19-42489247;