21-44287085-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000383.4(AIRE):c.415C>T(p.Arg139*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,216 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000383.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.415C>T | p.Arg139* | stop_gained | Exon 3 of 14 | 1 | NM_000383.4 | ENSP00000291582.5 | ||
AIRE | ENST00000527919.5 | n.576C>T | non_coding_transcript_exon_variant | Exon 3 of 14 | 2 | |||||
AIRE | ENST00000530812.5 | n.584C>T | non_coding_transcript_exon_variant | Exon 3 of 12 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000248 AC: 6AN: 242012Hom.: 0 AF XY: 0.0000225 AC XY: 3AN XY: 133410
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1459996Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726304
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74446
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:7
- -
- -
This sequence change creates a premature translational stop signal (p.Arg139*) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs121434256, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (PMID: 9856486, 22024611). ClinVar contains an entry for this variant (Variation ID: 3310). For these reasons, this variant has been classified as Pathogenic. -
- -
- -
Variant summary: AIRE c.415C>T (p.Arg139X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.5e-05 in 242012 control chromosomes (gnomAD). c.415C>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Autoimmune Polyglandular Syndrome Type 1 (e.g. Rosatelli_1998, Zaidi_2017). The variant has been found predominantly in individuals and families of Italian (Sardinian) origin therefore, suggesting it is a founder mutation. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
not provided Pathogenic:2
The R139X nonsense variant has been reported previously in association with APECED (Rosatelli et al., 1998; Giordano et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, the variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we consider the variant to be pathogenic. -
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at