Variant 1-160155114-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_144699.4(ATP1A4):c.277A>C(p.Thr93Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATP1A4
NM_144699.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Variant links:

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]

ATP1A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.39164802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A4	NM_144699.4 linkuse as main transcript	c.277A>C	p.Thr93Pro	missense_variant	3/22	ENST00000368081.9
ATP1A4	XM_011509582.2 linkuse as main transcript	c.100A>C	p.Thr34Pro	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A4	ENST00000368081.9 linkuse as main transcript	c.277A>C	p.Thr93Pro	missense_variant	3/22	1	NM_144699.4	P1	Q13733-1
ATP1A4	ENST00000477338.5 linkuse as main transcript	c.277A>C	p.Thr93Pro	missense_variant, NMD_transcript_variant	3/22	1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

332

AN:

138798

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00286

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00585

Gnomad ASJ

AF:

0.00153

Gnomad EAS

AF:

0.00235

Gnomad SAS

AF:

0.00163

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.00263

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000319

AC:

453

AN:

1418230

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

225

AN XY:

707116

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.0000904

Gnomad4 ASJ exome

AF:

0.000235

Gnomad4 EAS exome

AF:

0.000206

Gnomad4 SAS exome

AF:

0.000651

Gnomad4 FIN exome

AF:

0.000344

Gnomad4 NFE exome

AF:

0.000297

Gnomad4 OTH exome

AF:

0.000615

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00239

AC:

332

AN:

138904

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

195

AN XY:

67150

show subpopulations

Gnomad4 AFR

AF:

0.00285

Gnomad4 AMR

AF:

0.00584

Gnomad4 ASJ

AF:

0.00153

Gnomad4 EAS

AF:

0.00236

Gnomad4 SAS

AF:

0.00163

Gnomad4 FIN

AF:

0.00274

Gnomad4 NFE

AF:

0.00150

Gnomad4 OTH

AF:

0.00260

Alfa

AF:

0.0102

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.277A>C (p.T93P) alteration is located in exon 3 (coding exon 3) of the ATP1A4 gene. This alteration results from a A to C substitution at nucleotide position 277, causing the threonine (T) at amino acid position 93 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

0.045

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.038

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.99

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.48

Sift

Benign

0.046

Sift4G

Benign

0.24

Polyphen

0.60

Vest4

0.38

MutPred

0.37

Loss of phosphorylation at T93 (P = 0.0483);

MVP

0.84

MPC

0.49

ClinPred

0.63

GERP RS

3.3

Varity_R

0.50

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over