1-116373521-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_000701.8(ATP1A1):c.10G>C(p.Gly4Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000542 in 1,476,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: ATP1A1 NM_000701.8 missense, splice_region
• Scores: Splicing: ADA: 0.04979
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.819

Genes affected

ATP1A1 (HGNC:799): (ATPase Na+/K+ transporting subunit alpha 1) 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 1 subunit. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATP1A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.27977878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A1	NM_000701.8	c.10G>C	p.Gly4Arg	missense_variant, splice_region_variant	1/23	ENST00000295598.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A1	ENST00000295598.10	c.10G>C	p.Gly4Arg	missense_variant, splice_region_variant	1/23	1	NM_000701.8	P4
ATP1A1	ENST00000418797.5	c.-82+600G>C		intron_variant		3
ATP1A1	ENST00000488733.1	n.253G>C		splice_region_variant, non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000528 AC: 7 AN: 1325156 Hom.: 0 Cov.: 31 AF XY: 0.00000614 AC XY: 4 AN XY: 651672

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000572

Gnomad4 OTH exome AF: 0.0000182

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74160

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 28, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ATP1A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4 of the ATP1A1 protein (p.Gly4Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.0025	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.58	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.023	D
Sift4G	Benign	0.13	T
Polyphen		0.040	B
Vest4		0.14
MutPred		0.22		Loss of ubiquitination at K3 (P = 0.0134);
MVP		0.83
ClinPred		0.23	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.050
dbscSNV1_RF	Benign	0.37
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: rs1307008508; hg19: chr1-116916143;