rs121434254
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000383.4(AIRE):c.769C>T(p.Arg257Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,612,654 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00049 ( 1 hom. )
Consequence
AIRE
NM_000383.4 stop_gained
NM_000383.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 0.784
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]
Genome browser will be placed here
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 21-44289773-C-T is Pathogenic according to our data. Variant chr21-44289773-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44289773-C-T is described in Lovd as [Pathogenic]. Variant chr21-44289773-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.769C>T | p.Arg257Ter | stop_gained | 6/14 | ENST00000291582.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.769C>T | p.Arg257Ter | stop_gained | 6/14 | 1 | NM_000383.4 | P1 | |
AIRE | ENST00000527919.5 | n.1502C>T | non_coding_transcript_exon_variant | 6/14 | 2 | ||||
AIRE | ENST00000530812.5 | n.2519C>T | non_coding_transcript_exon_variant | 4/12 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000565 AC: 86AN: 152226Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
86
AN:
152226
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000745 AC: 185AN: 248166Hom.: 1 AF XY: 0.000755 AC XY: 102AN XY: 135114
GnomAD3 exomes
AF:
AC:
185
AN:
248166
Hom.:
AF XY:
AC XY:
102
AN XY:
135114
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000493 AC: 720AN: 1460428Hom.: 1 Cov.: 34 AF XY: 0.000494 AC XY: 359AN XY: 726516
GnomAD4 exome
AF:
AC:
720
AN:
1460428
Hom.:
Cov.:
34
AF XY:
AC XY:
359
AN XY:
726516
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000565 AC: 86AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.000753 AC XY: 56AN XY: 74366
GnomAD4 genome
?
AF:
AC:
86
AN:
152226
Hom.:
Cov.:
33
AF XY:
AC XY:
56
AN XY:
74366
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
2
ALSPAC
AF:
AC:
0
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
?
AF:
AC:
84
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:15
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg257*) 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 (rs121434254, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED) (PMID: 9398840, 20718774, 22024611). It is commonly reported in individuals of Finnish ancestry (PMID: 9398840). ClinVar contains an entry for this variant (Variation ID: 3307). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
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 | Genetics and Molecular Pathology, SA Pathology | Sep 29, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 29, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Aug 24, 2020 | This AIRE variant (rs121434254) is rare (<0.1%) in a large population dataset (gnomAD: 218/279538 total alleles; 0.08%; 1 homozygote) and has an entry in ClinVar. This variant has been reported previously in a homozygous or compound heterozygous state in multiple unrelated individuals affected with APS1. This nonsense variant results in a premature stop codon in exon 6 of 14 likely leading to nonsense mediated decay and lack of protein production. This variant alone is not expected to cause APS1. We consider c.769C>T to be pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.769C>T;p.(Arg257*) variant creates a premature translational stop signal in the AIRE gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 3307; PMID: 9398840; 20718774; 22024611; 9398840) - PS4. The variant is present at low allele frequencies population databases (rs121434254 - gnomAD 0.005649%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg257*) was detected in trans with a pathogenic variant (PMID: 9398840; 20718774; 22024611) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 05, 2020 | The c.769C>T, p.Arg257Ter nonsense variant identified in the AIRE gene has been reported previously in both the homozygous and compound heterozygous state in multiple unrelated individuals with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [PMID: 9398840; PMID: 25707324; PMID: 30863741; PMID: 31588815]. This variant is the most common Finnish pathogenic variant, present in 82% of Finnish APECED alleles, and is also common in the Northern Italian and Eastern European APECED patient populations [PMID: 9398840]. Functional studies have demonstrated that cells transfected with the p.Arg257Ter allele lack expression of mRNA from AIRE-dependent genes [PMID: 26084028]. This variant has 0.06%frequency (84 heterozygous) in gnomAD database indicating this is a rare allele. The detected nonsense substitution truncates the protein at codon 257, which is 289 amino acids from the end of the protein and expected to result in an absent protein product through nonsense-mediated mRNA decay [PMID: 24681721.] Based on the available evidence, the c.769C>T, p.Arg257Ter variant in the AIRE gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 19, 2019 | NM_000383.3(AIRE):c.769C>T(R257*) is classified as pathogenic in the context of type 1 autoimmune polyglandular syndrome. Sources cited for classification include the following: PMID 12050215, 20407228, 14974083, 9398839, 9398840, 18708298 and 10677297. Classification of NM_000383.3(AIRE):c.769C>T(R257*) 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2019 | Variant summary: AIRE c.769C>T (p.Arg257X), also known as the "Finnish major mutation", 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 0.00075 in 248166 control chromosomes in the gnomAD database, including 1 homozygote. c.769C>T has been reported in the literature in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1 (example, Aaltonen_1997, Giordano_2012, Cervato_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in lack of transcriptional regulation by mutant AIRE of KRT14, an AIRE-dependant gene as observed by a lack of mRNA expression in-vitro (example, Oftedal_2015). Four 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, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP4,PVS1,PS3,PM2. This variant was detected in homozygous state. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 14, 2019 | - - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2022 | Nonsense 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 demonstrate lack of expression of mRNA from AIRE-dependent genes (Oftedal et al., 2015); R257X variant is the most common Finnish pathogenic variant, present in 82% of Finnish APECED alleles, and is also common in the Northern Italian and Eastern European APECED patient populations (Finnish-German APECED Consortium 1997; Heino et al., 2001); This variant is associated with the following publications: (PMID: 22162465, 20718774, 24948345, 16965330, 11524733, 15886230, 11524731, 11298085, 22024611, 18616706, 9921903, 19807739, 12050215, 19863576, 25707324, 27065010, 27048654, 26891119, 14582926, 24158785, 18274776, 28458664, 30018023, 12951636, 11207636, 31588815, 30863741, 31956453, 33225392, 34078422, 34426522, 24493573, 32441320, 34235359, 26084028, 9398840) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | AIRE: PVS1, PM3:Strong, PM2:Supporting, PS3:Supporting - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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) | Oct 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 23, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
AIRE-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 15, 2023 | The AIRE c.769C>T variant is predicted to result in premature protein termination (p.Arg257*). This variant has been reported with a second AIRE variant in many unrelated individuals with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Nagamine et al. 1997. PubMed ID: 9398839; Finnish-German APECED Consortium. 1997. PubMed ID: 9398840; Björses et al. 2000. PubMed ID: 10677297; Stolarski et al. 2006. PubMed ID: 16965330; Podkrajsek et al. 2008. PubMed ID: 18682433; Orlova et al. 2010. PubMed ID: 20407228). In vitro experimental studies have demonstrated that this variant disrupts protein function (Björses et al. 2000. PubMed ID: 10677297; Halonen et al. 2004. PubMed ID: 14974083; Oftedal et al. 2015. PubMed ID: 26084028). This variant has also been observed in the heterozygous state without a second AIRE variant in some individuals with classic and atypical APECED with a proposed incomplete penetrance (Sedivá et al. 2002. PubMed ID: 12503856; Buzi et al. 2003. PubMed ID: 12843157; Orlova et al. 2010. PubMed ID: 20407228). However, there are many heterozygous individuals with no symptoms of APECED and an autosomal dominant mode of inheritance is not established. This variant is reported at a relatively high frequency (0.50% of alleles) in individuals of Finnish descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-45709656-C-T) but has been shown to be a founder mutation in this population (Finnish-German APECED Consortium. 1997. PubMed ID: 9398840). This variant is also interpreted as pathogenic or likely pathogenic by many labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3309). Nonsense variants in AIRE are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive AIRE-related disorders. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at