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
Consequence
NM_000383.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
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: 10AN: 1388486Hom.: 0 Cov.: 30 AF XY: 0.00000584 AC XY: 4AN XY: 685104
GnomAD4 genome Cov.: 33
ClinVar
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 | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at