rs146810389
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000383.4(AIRE):c.226G>A(p.Asp76Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D76D) has been classified as Likely benign.
Frequency
Consequence
NM_000383.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.226G>A | p.Asp76Asn | missense_variant | 2/14 | ENST00000291582.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.226G>A | p.Asp76Asn | missense_variant | 2/14 | 1 | NM_000383.4 | P1 | |
AIRE | ENST00000527919.5 | n.387G>A | non_coding_transcript_exon_variant | 2/14 | 2 | ||||
AIRE | ENST00000530812.5 | n.395G>A | non_coding_transcript_exon_variant | 2/12 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 250894Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135820
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1460748Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 726682
GnomAD4 genome ? AF: 0.000204 AC: 31AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74492
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 76 of the AIRE protein (p.Asp76Asn). This variant is present in population databases (rs146810389, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. ClinVar contains an entry for this variant (Variation ID: 458617). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIRE protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 31, 2018 | Variant summary: AIRE c.226G>A (p.Asp76Asn) results in a conservative amino acid change located in the HSR domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 276948 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (7.9e-05 vs 0.0028), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.226G>A in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at