rs747941115
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_ModeratePP5_Moderate
The NM_000383.4(AIRE):c.173C>G(p.Ala58Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,612,594 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. A58D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000383.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.173C>G | p.Ala58Gly | missense_variant | 2/14 | ENST00000291582.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.173C>G | p.Ala58Gly | missense_variant | 2/14 | 1 | NM_000383.4 | P1 | |
AIRE | ENST00000527919.5 | n.334C>G | non_coding_transcript_exon_variant | 2/14 | 2 | ||||
AIRE | ENST00000530812.5 | n.342C>G | non_coding_transcript_exon_variant | 2/12 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250242Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135634
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460388Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726468
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 07, 2022 | This variant disrupts the p.Ala58 amino acid residue in AIRE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26114819, 28911151, 30003128). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This missense change has been observed in individual(s) with clinical features of autoimmune polyendocrinopathy syndrome (Invitae). This variant is present in population databases (rs747941115, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 58 of the AIRE protein (p.Ala58Gly). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at