rs781829024

Positions:

• chr12-121626842-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The ENST00000617316.2(ORAI1):​c.100A>C​(p.Ser34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,477,300 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S34I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: ORAI1 ENST00000617316.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1 O:1
• Conservation: PhyloP100: 2.29

Genes affected

ORAI1 (HGNC:25896): (ORAI calcium release-activated calcium modulator 1) The protein encoded by this gene is a membrane calcium channel subunit that is activated by the calcium sensor STIM1 when calcium stores are depleted. This type of channel is the primary way for calcium influx into T-cells. Defects in this gene are a cause of immune dysfunction with T-cell inactivation due to calcium entry defect type 1 (IDTICED1). [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03208527).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000982 (121/123274) while in subpopulation NFE AF= 0.00189 (110/58166). AF 95% confidence interval is 0.0016. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORAI1	NM_032790.3	c.100A>C	p.Ser34Arg	missense_variant	1/3		NP_116179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORAI1	ENST00000617316.2	c.100A>C	p.Ser34Arg	missense_variant	1/3	1		ENSP00000482568	P1
ORAI1	ENST00000611718.1	n.27A>C		non_coding_transcript_exon_variant	1/2	5
ORAI1	ENST00000646827.1	n.293A>C		non_coding_transcript_exon_variant	1/2
ORAI1	ENST00000698901.1	n.334A>C		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.000982 AC: 121 AN: 123186 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000516 AC: 53 AN: 102706 Hom.: 0 AF XY: 0.000537 AC XY: 32 AN XY: 59604

Gnomad AFR exome AF: 0.000347

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000609

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00129 AC: 1742 AN: 1354026 Hom.: 1 Cov.: 29 AF XY: 0.00117 AC XY: 782 AN XY: 670502

Gnomad4 AFR exome AF: 0.000218

Gnomad4 AMR exome AF: 0.0000345

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.000146

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.000524

GnomAD4 genome AF: 0.000982 AC: 121 AN: 123274 Hom.: 0 Cov.: 30 AF XY: 0.000873 AC XY: 52 AN XY: 59572

Gnomad4 AFR AF: 0.000248

Gnomad4 AMR AF: 0.0000803

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00189

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000729 Hom.: 0

Bravo AF: 0.000722

ExAC AF: 0.000212 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency due to ORAI1 deficiency;C4014557:Myopathy, tubular aggregate, 2 Uncertain:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 02-15-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 34 of the ORAI1 protein (p.Ser34Arg). This variant is present in population databases (rs781829024, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ORAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 541941). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects ORAI1 function (PMID: 31036819). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jun 30, 2020	ORAI1 NM_032790.3 exon 1 p.Ser34Arg (c.100A>C): This variant has not been reported in the literature in association with human disease, but is present in 0.1% (71/52582) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-122064747-A-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:541941). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies predict that this variant will impact the protein (Zhang 2019 PMID:31036819). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -

Combined immunodeficiency due to ORAI1 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 18, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.037
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.93	D
Polyphen		0.84	P
MutPred		0.21		Loss of phosphorylation at S34 (P = 1e-04);
ClinPred		0.11	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.41
gMVP		0.67

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

Other links and lift over

dbSNP: rs781829024; hg19: chr12-122064747;