X-153536438-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_001001344.3(ATP2B3):c.191A>G(p.Lys64Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,197,896 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000026 ( 0 hom. 14 hem. )

Consequence

ATP2B3
NM_001001344.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.22

Variant links:

Genes affected

ATP2B3 (HGNC:816): (ATPase plasma membrane Ca2+ transporting 3) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 3. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14543435).

BP6

Variant X-153536438-A-G is Benign according to our data. Variant chrX-153536438-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3131547.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000258 (28/1084865) while in subpopulation SAS AF= 0.000482 (25/51872). AF 95% confidence interval is 0.000334. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2B3	NM_001001344.3 linkuse as main transcript	c.191A>G	p.Lys64Arg	missense_variant	3/22	ENST00000263519.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2B3	ENST00000263519.5 linkuse as main transcript	c.191A>G	p.Lys64Arg	missense_variant	3/22	1	NM_001001344.3	P1	Q16720-1

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

113031

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35179

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000360

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000390

AC:

AN:

153843

Hom.:

AF XY:

0.0000605

AC XY:

AN XY:

49549

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000371

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000258

AC:

AN:

1084865

Hom.:

Cov.:

AF XY:

0.0000395

AC XY:

AN XY:

354533

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000336

Gnomad4 SAS exome

AF:

0.000482

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000439

GnomAD4 genome

AF:

0.00000885

AC:

AN:

113031

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35179

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000360

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000754

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.086

T;.;.;.;T

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.018

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.7

L;L;L;L;L

MutationTaster

Benign

0.95

D;D;D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.21

T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.013

B;.;.;B;B

Vest4

0.072

MutPred

0.62

Loss of ubiquitination at K64 (P = 0.013);Loss of ubiquitination at K64 (P = 0.013);Loss of ubiquitination at K64 (P = 0.013);Loss of ubiquitination at K64 (P = 0.013);Loss of ubiquitination at K64 (P = 0.013);

MVP

0.87

MPC

0.48

ClinPred

0.10

GERP RS

4.6

Varity_R

0.15

gMVP

0.68

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