rs179363877

Positions:

• chr21-44286053-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.30

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 (HGNC:):

ACMG classification

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
AIRE	NM_000383.4	c.47C>T	p.Thr16Met	missense_variant	1/14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.47C>T	p.Thr16Met	missense_variant	1/14	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.208C>T		non_coding_transcript_exon_variant	1/14	2
AIRE	ENST00000530812.5	n.216C>T		non_coding_transcript_exon_variant	1/12	2

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

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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This 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 provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The 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 provided

literature only

UniProtKB/Swiss-Prot

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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

Other links and lift over

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