dbSNP rs755651840: ORAI3:p.Val255Met (chr16-30953719-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152288.3(ORAI3):c.763G>A(p.Val255Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,614,084 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 1 hom. )

Consequence

ORAI3
NM_152288.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.32

Variant links:

Genes affected

ORAI3 (HGNC:28185): (ORAI calcium release-activated calcium modulator 3) Predicted to enable store-operated calcium channel activity. Predicted to be involved in store-operated calcium entry. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ORAI3 links:

ENSG00000261487 (HGNC:):

ENSG00000261487 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORAI3	NM_152288.3 link	c.763G>A	p.Val255Met	missense_variant	Exon 2 of 2	ENST00000318663.5	NP_689501.1	Q9BRQ5A0A024QZA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORAI3	ENST00000318663.5 link	c.763G>A	p.Val255Met	missense_variant	Exon 2 of 2	1	NM_152288.3	ENSP00000322249.4		Q9BRQ5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251298

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135894

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:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000244

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763G>A (p.V255M) alteration is located in exon 2 (coding exon 2) of the ORAI3 gene. This alteration results from a G to A substitution at nucleotide position 763, causing the valine (V) at amino acid position 255 to be replaced by a methionine (M). 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

REVEL

Benign

0.23

Sift

Benign

0.082

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.35

MVP

0.52

MPC

0.68

ClinPred

0.35

GERP RS

5.6

Varity_R

0.12

gMVP

0.90

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