19-41981616-C-T

Variant names:

• chr19-41981616-C-T
• rs34578730
• NM_152296.5:c.1323G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_152296.5(ATP1A3):​c.1323G>A​(p.Ala441Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,614,192 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 31)
  • Exomes 𝑓: 0.010 (94 hom.)
• Consequence: ATP1A3 NM_152296.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 1.18

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]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 19-41981616-C-T is Benign according to our data. Variant chr19-41981616-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157924.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=1}. Variant chr19-41981616-C-T is described in Lovd as [Likely_benign]. Variant chr19-41981616-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0062 (944/152302) while in subpopulation NFE AF= 0.0107 (727/68036). AF 95% confidence interval is 0.01. There are 8 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 944 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.1323G>A	p.Ala441Ala	synonymous_variant	Exon 11 of 23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.1362G>A	p.Ala454Ala	synonymous_variant	Exon 11 of 23		NP_001243143.1
ATP1A3	NM_001256213.2	c.1356G>A	p.Ala452Ala	synonymous_variant	Exon 11 of 23		NP_001243142.1
ATP1A3	XM_047438862.1	c.1233G>A	p.Ala411Ala	synonymous_variant	Exon 11 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.1323G>A	p.Ala441Ala	synonymous_variant	Exon 11 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.1323G>A		non_coding_transcript_exon_variant	Exon 11 of 25			ENSP00000494711.1

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 943 AN: 152184 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00725 AC: 1824 AN: 251432 Hom.: 13 AF XY: 0.00756 AC XY: 1027 AN XY: 135898

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.0101 AC: 14798 AN: 1461890 Hom.: 94 Cov.: 32 AF XY: 0.0100 AC XY: 7278 AN XY: 727246

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.00350

Gnomad4 FIN exome AF: 0.00998

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00843

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152302 Hom.: 8 Cov.: 31 AF XY: 0.00606 AC XY: 451 AN XY: 74474

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00923

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00686 Hom.: 0

Bravo AF: 0.00570

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00916

EpiControl AF: 0.00877

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP1A3: BP4, BP7, BS1, BS2 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Dec 06, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 12, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alternating hemiplegia of childhood 2 Uncertain:1 Benign:1

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	11
DANN	Benign	0.65

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: rs34578730; hg19: chr19-42485768;