rs763954225
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The ENST00000291582.6(AIRE):c.1084G>T(p.Val362Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,554,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V362M) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000291582.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AIRE | NM_000383.4 | c.1084G>T | p.Val362Leu | missense_variant | 9/14 | ENST00000291582.6 | NP_000374.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.1084G>T | p.Val362Leu | missense_variant | 9/14 | 1 | NM_000383.4 | ENSP00000291582 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152036Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000590 AC: 9AN: 152488Hom.: 0 AF XY: 0.0000245 AC XY: 2AN XY: 81530
GnomAD4 exome AF: 0.0000171 AC: 24AN: 1401988Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 9AN XY: 691890
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152036Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74250
ClinVar
Submissions by phenotype
Polyglandular autoimmune syndrome, type 1 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2022 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 362 of the AIRE protein (p.Val362Leu). This variant is present in population databases (rs763954225, gnomAD 0.03%). 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: 528305). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at