19-41969507-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Moderate BP6_Moderate

The NM_152296.5(ATP1A3):c.2616C>G(p.Asn872Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.103

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a topological_domain Extracellular (size 51) in uniprot entity AT1A3_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ATP1A3
• BP4: Computational evidence support a benign effect (MetaRNN=0.13943118).
• BP6: Variant 19-41969507-G-C is Benign according to our data. Variant chr19-41969507-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 570707.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.2616C>G	p.Asn872Lys	missense_variant	19/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.2655C>G	p.Asn885Lys	missense_variant	19/23
ATP1A3	NM_001256213.2	c.2649C>G	p.Asn883Lys	missense_variant	19/23
ATP1A3	XM_047438862.1	c.2526C>G	p.Asn842Lys	missense_variant	19/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2616C>G	p.Asn872Lys	missense_variant	19/23		NM_152296.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 12 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.40	T;T;T;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.23	N
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.20	N;N;.;.;.
MutationTaster	Benign	0.87	D;D;D
PrimateAI	Uncertain	0.63	T
Polyphen		0.0	B;B;.;.;.
Vest4		0.17, 0.12, 0.17
MutPred		0.35		Gain of ubiquitination at N872 (P = 0.0311);Gain of ubiquitination at N872 (P = 0.0311);.;.;.;
MVP		0.61
MPC		1.5
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.18
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782057287; hg19: chr19-42473659;