rs1055311

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000383.4(AIRE):c.681C>T(p.Gly227Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,612,616 control chromosomes in the GnomAD database, including 57,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 4060 hom., cov: 33)

Exomes 𝑓: 0.26 ( 53911 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -2.24

Variant links:

Genes affected

AIRE (HGNC:360): (autoimmune regulator) This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). [provided by RefSeq, Jun 2012]

AIRE links:

AIRE (HGNC:):

AIRE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 21-44289685-C-T is Benign according to our data. Variant chr21-44289685-C-T is described in ClinVar as [Benign]. Clinvar id is 128339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44289685-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4 linkuse as main transcript	c.681C>T	p.Gly227Gly	synonymous_variant	6/14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AIRE	ENST00000291582.6 linkuse as main transcript	c.681C>T	p.Gly227Gly	synonymous_variant	6/14	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 linkuse as main transcript	n.1414C>T		non_coding_transcript_exon_variant	6/14	2
AIRE	ENST00000530812.5 linkuse as main transcript	n.2431C>T		non_coding_transcript_exon_variant	4/12	2

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30502

AN:

152040

Hom.:

4057

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0542

Gnomad AMI

AF:

0.303

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.202

GnomAD3 exomes

AF:

0.226

AC:

56380

AN:

249922

Hom.:

7482

AF XY:

0.228

AC XY:

30977

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.0479

Gnomad AMR exome

AF:

0.243

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.00501

Gnomad SAS exome

AF:

0.172

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.282

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.263

AC:

384500

AN:

1460458

Hom.:

53911

Cov.:

AF XY:

0.261

AC XY:

189649

AN XY:

726518

show subpopulations

Gnomad4 AFR exome

AF:

0.0431

Gnomad4 AMR exome

AF:

0.241

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.00524

Gnomad4 SAS exome

AF:

0.175

Gnomad4 FIN exome

AF:

0.316

Gnomad4 NFE exome

AF:

0.289

Gnomad4 OTH exome

AF:

0.228

GnomAD4 genome

AF:

0.201

AC:

30510

AN:

152158

Hom.:

4060

Cov.:

AF XY:

0.199

AC XY:

14821

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0540

Gnomad4 AMR

AF:

0.198

Gnomad4 ASJ

AF:

0.191

Gnomad4 EAS

AF:

0.00367

Gnomad4 SAS

AF:

0.169

Gnomad4 FIN

AF:

0.328

Gnomad4 NFE

AF:

0.287

Gnomad4 OTH

AF:

0.199

Alfa

AF:

0.244

Hom.:

6305

Bravo

AF:

0.185

Asia WGS

AF:

0.0720

AC:

248

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.265

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Polyglandular autoimmune syndrome, type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.90

DANN

Benign

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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