Genetic Variant ORAI3:p.Leu38Pro (chr16-30949402-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152288.3(ORAI3):c.113T>C(p.Leu38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,599,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ORAI3
NM_152288.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.98

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22935641).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152288.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORAI3	NM_152288.3	MANE Select	c.113T>C	p.Leu38Pro	missense	Exon 1 of 2	NP_689501.1	Q9BRQ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORAI3	ENST00000318663.5	TSL:1 MANE Select	c.113T>C	p.Leu38Pro	missense	Exon 1 of 2	ENSP00000322249.4	Q9BRQ5
ORAI3	ENST00000566237.1	TSL:5	c.113T>C	p.Leu38Pro	missense	Exon 1 of 3	ENSP00000457388.1	H3BTY7
ORAI3	ENST00000562699.1	TSL:2	c.113T>C	p.Leu38Pro	missense	Exon 1 of 2	ENSP00000457025.1	H3BT51

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

GnomAD2 exomes

AF:

0.0000885

AC:

AN:

214650

AF XY:

0.0000758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000589

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000180

AC:

AN:

1447102

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

719062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32968

American (AMR)

AF:

0.000601

AC:

AN:

43296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25756

East Asian (EAS)

AF:

0.00

AC:

AN:

38742

South Asian (SAS)

AF:

0.00

AC:

AN:

84178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106494

Other (OTH)

AF:

0.00

AC:

AN:

59746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41502

American (AMR)

AF:

0.000392

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000335

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

3.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.50

REVEL

Benign

0.27

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.015

Polyphen

0.98

Vest4

0.67

MutPred

0.37

Gain of disorder (P = 0.0242)

MVP

0.33

MPC

0.88

ClinPred

0.23

GERP RS

5.3

PromoterAI

0.012

Neutral

(source)

Varity_R

0.67

gMVP

0.63

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over