rs179363877

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000383.4(AIRE):​c.47C>T​(p.Thr16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000072 in 1,388,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T16R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

10
6
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 1.30
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a domain HSR (size 104) in uniprot entity AIRE_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_000383.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-44286053-C-G is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
Variant 21-44286053-C-T is Pathogenic according to our data. Variant chr21-44286053-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44286053-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AIRENM_000383.4 linkuse as main transcriptc.47C>T p.Thr16Met missense_variant 1/14 ENST00000291582.6 NP_000374.1 O43918-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AIREENST00000291582.6 linkuse as main transcriptc.47C>T p.Thr16Met missense_variant 1/141 NM_000383.4 ENSP00000291582.5 O43918-1
AIREENST00000527919.5 linkuse as main transcriptn.208C>T non_coding_transcript_exon_variant 1/142
AIREENST00000530812.5 linkuse as main transcriptn.216C>T non_coding_transcript_exon_variant 1/122

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000720
AC:
10
AN:
1388486
Hom.:
0
Cov.:
30
AF XY:
0.00000584
AC XY:
4
AN XY:
685104
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000835
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 11, 2021- -
Pathogenic, criteria provided, single submitterclinical testingNational Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of HealthSep 14, 2023- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 21, 2021- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 14, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 16 of the AIRE protein (p.Thr16Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (PMID: 11524733, 21932610, 25361846, 28911151). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68227). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIRE protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AIRE function (PMID: 14974083). For these reasons, this variant has been classified as Pathogenic. -
AIRE-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 17, 2024The AIRE c.47C>T variant is predicted to result in the amino acid substitution p.Thr16Met. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with autoimmune polyendocrinopathy syndrome (Table 1, Cihakova et al. 2001. PubMed ID: 11524733; Table 2, Podkrajsek et al. 2005. PubMed ID: 15886230; Table 1, Kollios et al. 2011. PubMed ID: 21932610). This variant has not been reported in a large population database, indicating this variant is rare. An in vitro experimental study suggests this variant disrupts the homomultimerization of the protein (Figure 5, Halonen et al. 2004. PubMed ID: 14974083). This variant is interpreted as pathogenic. -
not provided Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.68
T
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Uncertain
2.2
M
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-3.1
D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0070
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.71
MutPred
0.83
Loss of sheet (P = 0.0315);
MVP
0.99
MPC
0.57
ClinPred
0.99
D
GERP RS
3.8
Varity_R
0.36
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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.

Other links and lift over

dbSNP: rs179363877; hg19: chr21-45705936; COSMIC: COSV52394420; COSMIC: COSV52394420; API