Variant X-120362221-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001142447.3(ATP1B4):c.53G>A(p.Arg18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000852 in 1,208,577 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.000061 ( 0 hom. 23 hem. )

Consequence

ATP1B4
NM_001142447.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.914

Variant links:

Genes affected

ATP1B4 (HGNC:808): (ATPase Na+/K+ transporting family member beta 4) This gene has been found in all vertebrate genomes sequenced to date. However, this gene has undergone a change in function in placental mammals compared to other species. Specifically, in fish, avian, and amphibian species, this gene encodes plasma membrane-bound beta-subunits of Na,K-ATPase. In placental mammals, the encoded protein interacts with the nuclear transcriptional coregulator SKIP and may be involved in the regulation of TGF-beta signaling. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

ATP1B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014321208).

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP1B4	NM_001142447.3 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	1/8	ENST00000218008.8
ATP1B4	NM_012069.5 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	1/8
ATP1B4	XM_017029381.2 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1B4	ENST00000218008.8 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	1/8	1	NM_001142447.3	P1	Q9UN42-1
ATP1B4	ENST00000361319.3 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	1/8	1			Q9UN42-2
ATP1B4	ENST00000539306.5 linkuse as main transcript	c.53G>A	p.Arg18His	missense_variant	1/7	2

Frequencies

GnomAD3 genomes

AF:

0.000323

AC:

AN:

111434

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

33626

show subpopulations

Gnomad AFR

AF:

0.00105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000563

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

183296

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

67778

show subpopulations

Gnomad AFR exome

AF:

0.000988

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00130

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000611

AC:

AN:

1097089

Hom.:

Cov.:

AF XY:

0.0000635

AC XY:

AN XY:

362463

show subpopulations

Gnomad4 AFR exome

AF:

0.00110

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00106

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.000323

AC:

AN:

111488

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

33690

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000565

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

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

Sep 14, 2022

The c.53G>A (p.R18H) alteration is located in exon 1 (coding exon 1) of the ATP1B4 gene. This alteration results from a G to A substitution at nucleotide position 53, causing the arginine (R) at amino acid position 18 to be replaced by a histidine (H). 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

0.098

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0093

T;T;.

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.18

N;N;N

REVEL

Benign

0.048

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.051

T;D;D

Polyphen

0.0060

B;B;B

Vest4

0.22

MVP

0.76

MPC

0.20

ClinPred

0.020

GERP RS

1.7

Varity_R

0.084

gMVP

0.39

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

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