chr1-160155085-G-A

Variant names:

• chr1-160155085-G-A
• rs6427504
• NM_144699.4:c.248G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144699.4(ATP1A4):​c.248G>A​(p.Gly83Asp) variant causes a missense change. The variant allele was found at a frequency of 0.708 in 1,612,916 control chromosomes in the GnomAD database, including 405,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G83R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.72 (39744 hom., cov: 30)
  • Exomes 𝑓: 0.71 (365457 hom.)
• Consequence: ATP1A4 NM_144699.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.30
• Publications: 32 publications found

Genes affected

ATP1A4 (HGNC:14073): (ATPase Na+/K+ transporting subunit alpha 4) 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 4 subunit. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.241309E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A4	NM_144699.4	c.248G>A	p.Gly83Asp	missense_variant	Exon 3 of 22	ENST00000368081.9	NP_653300.2
ATP1A4	XM_011509582.2	c.71G>A	p.Gly24Asp	missense_variant	Exon 2 of 21		XP_011507884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A4	ENST00000368081.9	c.248G>A	p.Gly83Asp	missense_variant	Exon 3 of 22	1	NM_144699.4	ENSP00000357060.4
ATP1A4	ENST00000477338.5	n.248G>A		non_coding_transcript_exon_variant	Exon 3 of 22	1		ENSP00000434272.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109577 AN: 151708 Hom.: 39705 Cov.: 30

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.763

GnomAD2 exomes AF: 0.697 AC: 175081 AN: 251294 AF XY: 0.695

Gnomad AFR exome AF: 0.752

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.714

Gnomad EAS exome AF: 0.669

Gnomad FIN exome AF: 0.666

Gnomad NFE exome AF: 0.714

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.707 AC: 1032523 AN: 1461090 Hom.: 365457 Cov.: 53 AF XY: 0.706 AC XY: 513057 AN XY: 726878

African (AFR) AF: 0.757 AC: 25344 AN: 33470

American (AMR) AF: 0.688 AC: 30755 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 18662 AN: 26130

East Asian (EAS) AF: 0.685 AC: 27170 AN: 39684

South Asian (SAS) AF: 0.649 AC: 55921 AN: 86220

European-Finnish (FIN) AF: 0.672 AC: 35890 AN: 53418

Middle Eastern (MID) AF: 0.750 AC: 4312 AN: 5752

European-Non Finnish (NFE) AF: 0.713 AC: 791857 AN: 1111324

Other (OTH) AF: 0.706 AC: 42612 AN: 60372

GnomAD4 genome AF: 0.722 AC: 109675 AN: 151826 Hom.: 39744 Cov.: 30 AF XY: 0.720 AC XY: 53423 AN XY: 74170

African (AFR) AF: 0.754 AC: 31214 AN: 41378

American (AMR) AF: 0.744 AC: 11343 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2449 AN: 3472

East Asian (EAS) AF: 0.681 AC: 3500 AN: 5140

South Asian (SAS) AF: 0.647 AC: 3113 AN: 4808

European-Finnish (FIN) AF: 0.653 AC: 6864 AN: 10512

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48725 AN: 67950

Other (OTH) AF: 0.763 AC: 1612 AN: 2112

Alfa AF: 0.718 Hom.: 136238

Bravo AF: 0.725

TwinsUK AF: 0.708 AC: 2624

ALSPAC AF: 0.725 AC: 2793

ESP6500AA AF: 0.750 AC: 3305

ESP6500EA AF: 0.715 AC: 6152

ExAC AF: 0.698 AC: 84690

Asia WGS AF: 0.697 AC: 2421 AN: 3478

EpiCase AF: 0.721

EpiControl AF: 0.723

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.71
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0000052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-3.1	N
PhyloP100		6.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	4.6	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.22
ClinPred		0.0072	T
GERP RS		4.5
Varity_R		0.036
gMVP		0.37
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6427504; hg19: chr1-160124875; COSMIC: COSV63625853;