21-44288401-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000383.4(AIRE):c.595G>A(p.Val199Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,612,754 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000383.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AIRE | ENST00000291582.6 | c.595G>A | p.Val199Ile | missense_variant | Exon 5 of 14 | 1 | NM_000383.4 | ENSP00000291582.5 | ||
AIRE | ENST00000527919.5 | n.1139G>A | non_coding_transcript_exon_variant | Exon 4 of 14 | 2 | |||||
AIRE | ENST00000530812.5 | n.1147G>A | non_coding_transcript_exon_variant | Exon 4 of 12 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00378 AC: 575AN: 152208Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00120 AC: 300AN: 250342Hom.: 0 AF XY: 0.000973 AC XY: 132AN XY: 135650
GnomAD4 exome AF: 0.000615 AC: 898AN: 1460428Hom.: 5 Cov.: 31 AF XY: 0.000575 AC XY: 418AN XY: 726544
GnomAD4 genome AF: 0.00377 AC: 574AN: 152326Hom.: 2 Cov.: 33 AF XY: 0.00379 AC XY: 282AN XY: 74478
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
- -
Variant summary: AIRE c.595G>A (p.Val199Ile) results in a conservative amino acid change located in the SAND domain (IPR000770) 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 0.0015 in 281720 control chromosomes (gnomAD), predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance and three as benign. Based on the evidence outlined above, the variant was classified as benign. -
- -
Polyglandular autoimmune syndrome, type 1 Benign:2
- -
- -
not provided Benign:1
AIRE: BP4, BS1 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at