21-44286007-A-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong
The NM_000383.4(AIRE):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000458 in 1,529,884 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 (★★).
Frequency
Consequence
NM_000383.4 initiator_codon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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AIRE | ENST00000291582.6 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 14 | 1 | NM_000383.4 | ENSP00000291582.5 | ||
AIRE | ENST00000527919.5 | n.162A>T | non_coding_transcript_exon_variant | Exon 1 of 14 | 2 | |||||
AIRE | ENST00000530812.5 | n.170A>T | non_coding_transcript_exon_variant | Exon 1 of 12 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151882Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000363 AC: 5AN: 1378002Hom.: 0 Cov.: 30 AF XY: 0.00000441 AC XY: 3AN XY: 679800
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151882Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74192
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:4
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For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3314). Disruption of the initiator codon has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 16965330, 19758376, 20407228, 28446514, 28911151). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the AIRE mRNA. The next in-frame methionine is located at codon 184. -
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not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at