rs1231469574
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5
The NM_000383.4(AIRE):c.22C>T(p.Arg8Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,534,766 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000383.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.22C>T | p.Arg8Cys | missense_variant | 1/14 | ENST00000291582.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.22C>T | p.Arg8Cys | missense_variant | 1/14 | 1 | NM_000383.4 | P1 | |
AIRE | ENST00000527919.5 | n.183C>T | non_coding_transcript_exon_variant | 1/14 | 2 | ||||
AIRE | ENST00000530812.5 | n.191C>T | non_coding_transcript_exon_variant | 1/12 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000758 AC: 1AN: 131876Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 72076
GnomAD4 exome AF: 0.0000145 AC: 20AN: 1382642Hom.: 0 Cov.: 30 AF XY: 0.0000132 AC XY: 9AN XY: 682040
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74312
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 18, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 8 of the AIRE protein (p.Arg8Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 17118990, 27253668). ClinVar contains an entry for this variant (Variation ID: 552873). 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%. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 03, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at