chr21-44286994-GC-G
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000383.4(AIRE):βc.328delβ(p.Arg110GlyfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
AIRE
NM_000383.4 frameshift
NM_000383.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.802
Genes affected
AIRE (HGNC:360): (autoimmune regulator) This gene encodes a transcriptional regulator that forms nuclear bodies and interacts with the transcriptional coactivator CREB binding protein. The encoded protein plays an important role in immunity by regulating the expression of autoantigens and negative selection of autoreactive T-cells in the thymus. Mutations in this gene cause the rare autosomal-recessive systemic autoimmune disease termed autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED). [provided by RefSeq, Jun 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 21-44286994-GC-G is Pathogenic according to our data. Variant chr21-44286994-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.328del | p.Arg110GlyfsTer37 | frameshift_variant | 3/14 | ENST00000291582.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.328del | p.Arg110GlyfsTer37 | frameshift_variant | 3/14 | 1 | NM_000383.4 | P1 | |
AIRE | ENST00000527919.5 | n.489del | non_coding_transcript_exon_variant | 3/14 | 2 | ||||
AIRE | ENST00000530812.5 | n.497del | non_coding_transcript_exon_variant | 3/12 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245766Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134340
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460482Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726524
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change creates a premature translational stop signal (p.Arg110Glyfs*37) 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 (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autoimmune polyendocrinopathy syndrome (PMID: 24948345). ClinVar contains an entry for this variant (Variation ID: 553161). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Sep 14, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 23, 2021 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at