rs386833675

Variant names:

• chr21-44291179-TGCCTGTCCCCTCC-T
• rs386833675
• NM_000383.4:c.967_979delCTGTCCCCTCCGC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000383.4(AIRE):​c.967_979delCTGTCCCCTCCGC​(p.Leu323SerfsTer51) variant causes a frameshift change. The variant allele was found at a frequency of 0.00103 in 1,606,780 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: AIRE NM_000383.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 7.08

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]

ACMG classification

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 rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.967_979delCTGTCCCCTCCGC	p.Leu323SerfsTer51	frameshift_variant	Exon 8 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.967_979delCTGTCCCCTCCGC	p.Leu323SerfsTer51	frameshift_variant	Exon 8 of 14	1	NM_000383.4	ENSP00000291582.5

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152132 Hom.: 0 Cov.: 33

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.: 0 AF XY: 0.000491 AC XY: 65 AN XY: 132390

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.: 3 AF XY: 0.00104 AC XY: 753 AN XY: 723754

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: 89 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74450

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.: 0

Bravo AF: 0.000650

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:16 Other:1

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Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 02, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Sep 14, 2023

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 17, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000383.3(AIRE):c.967_979del13(L323Sfs*51) 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(L323Sfs*51) 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. -

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 autosomal recessive 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. -

Feb 14, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.967_979del;p.(Leu323Serfs*51) 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.(Leu323Serfs*51) 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. -

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.136%). Predicted Consequence/Location: Intron variant Damaging effect on gene or gene product predicted by in silico programs is uncertain [Splice AI: 0.10 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 28459997, 30323018, 30847471). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 28459997). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000445922 /PMID: 27029625 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 29, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 22, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia (MIM#240300). While most variants associated with disease are loss of function, one missense variant has been reported to have a dominant negative effect (OMIM, PMID: 16114041). (I) 0108 - This gene is associated with both recessive and dominant disease. Although this disease is most commonly inherited in an autosomal recessive pattern, one family has been reported with autosomal dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (138 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is commonly reported in individuals with autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome (ClinVar, PMID: 27588307). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 24, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:8

Nov 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP4, PM3_very_strong, PVS1 -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AIRE: PVS1, PM3:Strong, PM2:Supporting -

Mar 05, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 27, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AIRE-related disorder Pathogenic:1

Jul 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 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

Nov 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386833675; hg19: chr21-45711062;