chr21-44285985-CCCGGGTCCCCGCGCCCACCCCATGGCGACGGACGCGGCGCTACG-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000383.4(AIRE):c.-17_27del variant causes a start lost, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
AIRE
NM_000383.4 start_lost, 5_prime_UTR
NM_000383.4 start_lost, 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.05
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 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 21-44285985-CCCGGGTCCCCGCGCCCACCCCATGGCGACGGACGCGGCGCTACG-C is Pathogenic according to our data. Variant chr21-44285985-CCCGGGTCCCCGCGCCCACCCCATGGCGACGGACGCGGCGCTACG-C is described in ClinVar as [Pathogenic]. Clinvar id is 954404.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.-17_27del | start_lost, 5_prime_UTR_variant | 1/14 | ENST00000291582.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.-17_27del | start_lost, 5_prime_UTR_variant | 1/14 | 1 | NM_000383.4 | P1 | ||
AIRE | ENST00000527919.5 | n.145_188del | non_coding_transcript_exon_variant | 1/14 | 2 | ||||
AIRE | ENST00000530812.5 | n.153_196del | non_coding_transcript_exon_variant | 1/12 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2019 | This sequence change affects the initiator methionine of the AIRE mRNA. The next in-frame methionine is located at codon 184. For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in several individuals affected with autoimmune polyendocrinopathy syndrome (PMID: 28911151, 20407228, 19758376, 28446514). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at