rs121434254

chr21-44289773-C-Tchr21-44289773-C-Gchr21-44289773-C-A

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 0.784

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:

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 linkuse as main transcript	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 linkuse as main transcript	c.769C>T	p.Arg257Ter	stop_gained	6/14	1	NM_000383.4	P1	O43918-1
AIRE	ENST00000527919.5 linkuse as main transcript	n.1502C>T		non_coding_transcript_exon_variant	6/14	2
AIRE	ENST00000530812.5 linkuse as main transcript	n.2519C>T		non_coding_transcript_exon_variant	4/12	2

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00461

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000745

AC:

185

AN:

248166

Hom.:

AF XY:

0.000755

AC XY:

102

AN XY:

135114

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00505

Gnomad NFE exome

AF:

0.000610

Gnomad OTH exome

AF:

0.000659

GnomAD4 exome

AF:

0.000493

AC:

720

AN:

1460428

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

359

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00472

Gnomad4 NFE exome

AF:

0.000402

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000565

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00461

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000495

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000693

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1

Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 14, 2019	- -
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	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	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Sep 14, 2023	- -
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. -
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	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 29, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
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. -

not provided

Pathogenic:6

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.62

MutationTaster

Benign

1.0

Vest4

0.75

GERP RS

2.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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