Variant X-120366784-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001142447.3(ATP1B4):c.323G>A(p.Ser108Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000097 in 1,206,219 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., 17 hem., cov: 22)

Exomes 𝑓: 0.000058 ( 0 hom. 16 hem. )

Consequence

ATP1B4
NM_001142447.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.79

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20252043).

BS2

High Hemizygotes in GnomAd4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ATP1B4	NM_001142447.3 linkuse as main transcript	c.323G>A	p.Ser108Asn	missense_variant	2/8	ENST00000218008.8	NP_001135919.1
ATP1B4	XM_017029381.2 linkuse as main transcript	c.323G>A	p.Ser108Asn	missense_variant	2/5		XP_016884870.1
ATP1B4	NM_012069.5 linkuse as main transcript	c.316+7G>A		splice_region_variant, intron_variant			NP_036201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1B4	ENST00000218008.8 linkuse as main transcript	c.323G>A	p.Ser108Asn	missense_variant	2/8	1	NM_001142447.3	ENSP00000218008	P1	Q9UN42-1
ATP1B4	ENST00000361319.3 linkuse as main transcript	c.316+7G>A		splice_region_variant, intron_variant		1		ENSP00000355346		Q9UN42-2
ATP1B4	ENST00000539306.5 linkuse as main transcript	c.323G>A	p.Ser108Asn	missense_variant	2/7	2		ENSP00000443334

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

112092

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

34234

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.000663

GnomAD3 exomes

AF:

0.000156

AC:

AN:

179969

Hom.:

AF XY:

0.0000910

AC XY:

AN XY:

65903

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000585

AC:

AN:

1094074

Hom.:

Cov.:

AF XY:

0.0000445

AC XY:

AN XY:

359796

show subpopulations

Gnomad4 AFR exome

AF:

0.00216

Gnomad4 AMR exome

AF:

0.0000285

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:

0.000131

GnomAD4 genome

AF:

0.000473

AC:

AN:

112145

Hom.:

Cov.:

AF XY:

0.000496

AC XY:

AN XY:

34297

show subpopulations

Gnomad4 AFR

AF:

0.00162

Gnomad4 AMR

AF:

0.000188

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:

0.000655

Alfa

AF:

0.000422

Hom.:

Bravo

AF:

0.000563

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

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

Apr 04, 2024

The c.323G>A (p.S108N) alteration is located in exon 2 (coding exon 2) of the ATP1B4 gene. This alteration results from a G to A substitution at nucleotide position 323, causing the serine (S) at amino acid position 108 to be replaced by an asparagine (N). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.3

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.28

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.036

D;D

Polyphen

1.0

D;D

Vest4

0.69

MVP

0.69

MPC

0.65

ClinPred

0.094

GERP RS

5.3

Varity_R

0.75

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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