rs179363889
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000383.4(AIRE):c.1616C>T(p.Pro539Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,284 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P539T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000383.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.1616C>T | p.Pro539Leu | missense_variant | 14/14 | ENST00000291582.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.1616C>T | p.Pro539Leu | missense_variant | 14/14 | 1 | NM_000383.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249350Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135500
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1460076Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726386
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 29, 2022 | - - |
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 | Invitae | Sep 08, 2023 | ClinVar contains an entry for this variant (Variation ID: 68218). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIRE protein function. Experimental studies have shown that this missense change affects AIRE function (PMID: 17675238). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (PMID: 11836330, 15811934, 17289071, 21295522, 28446514). This variant is present in population databases (rs179363889, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 539 of the AIRE protein (p.Pro539Leu). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 10, 2017 | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2021 | Published functional studies demonstrate a reduction of transactivation activity compared to normal protein (Meloni et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21295522, 30018023, 15511668, 28446514, 23000069, 12398240, 17289071, 18713028, 15751604, 11836330, 17675238, 15811934) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at