rs3825175

chr12-121641535-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032790.3(ORAI1):c.801T>C(p.Thr267=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,108 control chromosomes in the GnomAD database, including 164,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20788 hom., cov: 33)
  • Exomes 𝑓: 0.44 (144079 hom.)
• Consequence: ORAI1 NM_032790.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.776

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-121641535-T-C is Benign according to our data. Variant chr12-121641535-T-C is described in ClinVar as [Benign]. Clinvar id is 379394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-121641535-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.776 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORAI1	NM_032790.3	c.801T>C	p.Thr267=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORAI1	ENST00000617316.2	c.798T>C	p.Thr266=	synonymous_variant	3/3	1		P1
ORAI1	ENST00000646827.1	n.996T>C		non_coding_transcript_exon_variant	2/2
ORAI1	ENST00000698901.1	n.920T>C		non_coding_transcript_exon_variant	2/2
ORAI1	ENST00000611718.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.507 AC: 77088 AN: 152052 Hom.: 20732 Cov.: 33

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.462

GnomAD3 exomes AF: 0.469 AC: 116387 AN: 248184 Hom.: 28240 AF XY: 0.466 AC XY: 62793 AN XY: 134854

Gnomad AFR exome AF: 0.693

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.596

Gnomad SAS exome AF: 0.509

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.440 AC: 642210 AN: 1460938 Hom.: 144079 Cov.: 65 AF XY: 0.441 AC XY: 320366 AN XY: 726846

Gnomad4 AFR exome AF: 0.699

Gnomad4 AMR exome AF: 0.487

Gnomad4 ASJ exome AF: 0.367

Gnomad4 EAS exome AF: 0.610

Gnomad4 SAS exome AF: 0.511

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.441

GnomAD4 genome AF: 0.507 AC: 77215 AN: 152170 Hom.: 20788 Cov.: 33 AF XY: 0.507 AC XY: 37740 AN XY: 74402

Gnomad4 AFR AF: 0.688

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.515

Gnomad4 FIN AF: 0.423

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.462

Alfa AF: 0.458 Hom.: 9327

Bravo AF: 0.517

Asia WGS AF: 0.580 AC: 2020 AN: 3478

EpiCase AF: 0.407

EpiControl AF: 0.411

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 76% of patients studied by a panel of primary immunodeficiencies. Number of patients: 72. Only high quality variants are reported. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.4
Dann	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3825175; hg19: chr12-122079441; COSMIC: COSV57490887; COSMIC: COSV57490887;