rs763695515
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000383.4(AIRE):βc.1295_1296insAβ(p.Arg433fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,596,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. A432A?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000383.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.1295_1296insA | p.Arg433fs | frameshift_variant | 11/14 | ENST00000291582.6 | NP_000374.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.1295_1296insA | p.Arg433fs | frameshift_variant | 11/14 | 1 | NM_000383.4 | ENSP00000291582.5 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000126 AC: 3AN: 238096Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 130174
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1444356Hom.: 0 Cov.: 33 AF XY: 0.00000556 AC XY: 4AN XY: 718966
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74260
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 07, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 20, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 585381). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. This variant is present in population databases (rs763695515, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg433Alafs*71) 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). - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 03, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at