rs150785666

Positions:

• chr19-41981552-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Moderate BS1 BS2

The NM_152296.5(ATP1A3):​c.1387C>T​(p.Arg463Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,614,084 control chromosomes in the GnomAD database, including 2 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 0.00048 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 2.72

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 -9 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A3. . Gene score misZ 6.3327 (greater than the threshold 3.09). Trascript score misZ 9.1232 (greater than threshold 3.09). GenCC has associacion of gene with dystonia 12, alternating hemiplegia of childhood 2, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99, alternating hemiplegia of childhood, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 1, encephalopathy, acute, infection-induced.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20119265).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00048 (73/152190) while in subpopulation NFE AF= 0.000808 (55/68038). AF 95% confidence interval is 0.000638. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.1387C>T	p.Arg463Cys	missense_variant	11/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.1426C>T	p.Arg476Cys	missense_variant	11/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.1420C>T	p.Arg474Cys	missense_variant	11/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.1297C>T	p.Arg433Cys	missense_variant	11/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.1387C>T	p.Arg463Cys	missense_variant	11/23		NM_152296.5	ENSP00000498113

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000465 AC: 117 AN: 251494 Hom.: 0 AF XY: 0.000419 AC XY: 57 AN XY: 135922

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000664 AC: 971 AN: 1461894 Hom.: 2 Cov.: 32 AF XY: 0.000616 AC XY: 448 AN XY: 727248

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000808

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.000525 AC XY: 39 AN XY: 74348

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000622 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.000709

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dystonia 12 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 06, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3. -
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. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ATP1A3: PP2, BS2 -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 10, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2016

The R463C variant in the ATP1A3 gene has not been previously reported as a pathogenic or benign variant to our knowledge. The R463C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R463C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Alternating hemiplegia of childhood 2 Benign:1

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ATP1A3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;D;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.56	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.9	L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.9	.;D;.;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Uncertain	0.010	.;D;D;D;D
Polyphen		0.68	P;P;.;.;.
Vest4		0.40, 0.42, 0.40
MVP		0.91
MPC		2.8
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.67
gMVP		0.92

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: rs150785666; hg19: chr19-42485704; COSMIC: COSV57489265; COSMIC: COSV57489265;