Variant rs386833675 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 21-44291179-TGCCTGTCCCCTCC-T is Pathogenic according to our data. Variant chr21-44291179-TGCCTGTCCCCTCC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44291179-TGCCTGTCCCCTCC-T is described in Lovd as [Pathogenic]. Variant chr21-44291179-TGCCTGTCCCCTCC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4 linkuse as main transcript	c.967_979del	p.Leu323SerfsTer51	frameshift_variant	8/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6 linkuse as main transcript	c.967_979del	p.Leu323SerfsTer51	frameshift_variant	8/14	1	NM_000383.4	P1	O43918-1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000506

AC:

123

AN:

242922

Hom.:

AF XY:

0.000491

AC XY:

AN XY:

132390

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000172

Gnomad NFE exome

AF:

0.000989

Gnomad OTH exome

AF:

0.000997

GnomAD4 exome

AF:

0.00108

AC:

1570

AN:

1454530

Hom.:

AF XY:

0.00104

AC XY:

753

AN XY:

723754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000213

Gnomad4 NFE exome

AF:

0.00132

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.000585

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.000650

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1

Pathogenic:14Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_000383.3(AIRE):c.967_979del13(L323Sfs51) is classified as pathogenic in the context of autoimmune polyglandular syndrome type 1. Sources cited for classification include the following: PMID 17220063, 12050215, 17118990, 9921903, 9837820, 21295522, 17118990 and 12050215. Classification of NM_000383.3(AIRE):c.967_979del13(L323Sfs51) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 22, 2022	The p.Leu323SerfsX51 variant in AIRE is a well-established pathogenic variant, which represents the most common variant identified in Anglo-American autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients (Heino 2001 PMID: 11524731, Ferre 2016 PMID: 27588307). It has also been identified in 0.096% (121/125552) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 323 and leads to a premature termination codon 51 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the AIRE gene is an established disease mechanism in autosomal recessive APECED. Finally, the p.Leu323SerfsX51 has been reported as Pathogenic by multiple clinical labs in ClinVar (Variation ID 3309). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive APECED. ACMG/AMP Criteria applied: ACMG/AMP criteria applied: PVS1, PM3_VeryStrong. -
Pathogenic, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Sep 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.967_979del;p.(Leu323Serfs51) is a null frameshift variant in the AIRE gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 3309; PMID: 11524731; 9837820; 27588307) - PS4. The variant is present at low allele frequencies population databases (rs386833675 - gnomAD 0.0005850%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu323Serfs51) was detected in trans with a pathogenic variant (PMID: 11524731; 9837820; 27588307) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 11-09-2020 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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.050%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003309). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	This sequence change creates a premature translational stop signal (p.Leu323Serfs*51) in the AIRE gene. This variant causes a frameshift starting with codon Leucine 323, changes this amino acid to Serine residue, and creates a premature Stop codon at position 51 of the new reading frame, denoted p.Leu323SerfsTer51. It is expected to result in an absent or disrupted protein product. This variant has been reported in numerous individuals and families affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and is the most common variant found in affected individuals of British or Anglo-American ancestry (Heino, Maarit, et al, Pearce, Simon HS, et al). An experimental study has shown that this sequence change has a dominant negative effect on the gene regulation of tested AIRE-regulated genes (Oftedal, Bergithe E., et al). This variant has been reported to the ClinVar database as Pathogenic/ Likely pathogenic. The variant is reported with the allele frequency of 0.05032% in gnomAD Exome is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 24, 2020	Variant summary: AIRE c.967_979del13 (p.Leu323SerfsX51) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00051 in 243022 control chromosomes. c.967_979del13 has been widely reported in the literature as a frequent mutation in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1 (example, Wang_1998, Dominguez_2006). These data indicate that the variant is very likely to be associated with disease. A mice model of this 13-bp deletion displaying a mild autoimmune phenotype characterized by a disturbance of medullary epithelial compartment, increased levels of activated T cells and autoantibodies against multiple organs has been reported (Hubert_2009). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Leu323Serfs*51) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs779937061, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and is the most common variant found in affected individuals of British or Anglo-American ancestry (PMID: 9837820, 11524731, 27588307). It has also been observed to segregate with disease in related individuals. This variant is also known as c.964del13, c.967_979del13, p.C322del13, or c.1094_1106del. ClinVar contains an entry for this variant (Variation ID: 3309). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AIRE: PM3:Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2021	Considered to be a founder variant in the Anglo-American population (Pearce et al., 1998; Heino et al., 2001); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies indicate the variant may have a minor dominant negative effect, which in heterozygotes could lead to atypical phenotypes with later onset and reduced penetrance (Oftedal et al., 2015); This variant is associated with the following publications: (PMID: 24948345, 19265170, 10677297, 27588307, 28769929, 28911151, 27219120, 11916620, 11207636, 19807739, 23620608, 9921903, 10720083, 17118990, 14557425, 26912174, 25707324, 9398840, 27253668, 28323927, 11298085, 31589614, 9837820, 26084028, 11524731) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 05, 2018	- -

AIRE-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2023

The AIRE c.967_979del13 variant is predicted to result in a frameshift and premature protein termination (p.Leu323Serfs*51). This variant has been reported in many unrelated individuals to be pathogenic for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Finnish-German APECED Consortium. 1997. PubMed ID: 9398840). This variant is reported in 0.096% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-45711062-TGCCTGTCCCCTCC-T) and is interpreted as pathogenic or likely pathogenic by many labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3309). Frameshift variants in AIRE are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive APECED. -

Autoimmune polyglandular syndrome type 1, with reversible metaphyseal dysplasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

rs386833675

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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