chr21-44286050-G-T

Variant names:

• chr21-44286050-G-T
• rs179363876
• NM_000383.4:c.44G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP3_Strong PP5_Moderate

The NM_000383.4(AIRE):​c.44G>T​(p.Arg15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000648 in 1,387,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain HSR (size 104) in uniprot entity AIRE_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_000383.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-44286049-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 21-44286050-G-T is Pathogenic according to our data. Variant chr21-44286050-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 68226.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-44286050-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.44G>T	p.Arg15Leu	missense_variant	Exon 1 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.44G>T	p.Arg15Leu	missense_variant	Exon 1 of 14	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.205G>T		non_coding_transcript_exon_variant	Exon 1 of 14	2
AIRE	ENST00000530812.5	n.213G>T		non_coding_transcript_exon_variant	Exon 1 of 12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000648 AC: 9 AN: 1387840 Hom.: 0 Cov.: 30 AF XY: 0.00000584 AC XY: 4 AN XY: 684742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000251

Gnomad4 NFE exome AF: 0.00000649

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:2

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 15 of the AIRE protein (p.Arg15Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy type 1 (PMID: 9837820). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68226). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt AIRE protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AIRE function (PMID: 14974083, 15712268). For these reasons, this variant has been classified as Pathogenic. -

Apr 14, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.93		Loss of MoRF binding (P = 0.0094);
MVP		1.0
MPC		0.62
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs179363876; hg19: chr21-45705933;