chr21-44286698-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_000383.4(AIRE):c.274C>T(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,978 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.0830

Variant links:

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]

AIRE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

PP5

Variant 21-44286698-C-T is Pathogenic according to our data. Variant chr21-44286698-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 379319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44286698-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.274C>T	p.Arg92Trp	missense_variant	Exon 2 of 14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AIRE	ENST00000291582.6 link	c.274C>T	p.Arg92Trp	missense_variant	Exon 2 of 14	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 link	n.435C>T		non_coding_transcript_exon_variant	Exon 2 of 14	2
AIRE	ENST00000530812.5 link	n.443C>T		non_coding_transcript_exon_variant	Exon 2 of 12	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460682

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726644

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000272

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1

Pathogenic:7

Feb 20, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AIRE c.274C>T (p.Arg92Trp) results in a non-conservative amino acid change located in the HSR domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276962 control chromosomes (gnomAD and publication). c.274C>T has been reported in the literature in multiple affected individuals with features of Autoimmune Polyglandular Syndrome Type 1 (Zaidi_2017, Al-Mousa_2016, Magitta_2008). These data indicate that the variant is very likely to be associated with disease. The variant was also identified in our laboratory as a compound heterozygote with another variant (c.967_979delCTGTCCCCTCCGC, p.Leu323fsX51) in a patient presenting with features of hyperparathyroidism, Addisons disease, hepatitis, esophagitis, asplenia, poor dental enamel, growth hormone deficiency, and retinal dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (1x) and once as likely pathogenic. This variant was previously classified conservatively as a VUS-possibly pathogenic variant by our laboratory in 2016. At-least two other reports reporting its presence in 4 additional affected individuals have been reported since its original classification by our laboratory. Based on all the evidence outlined above, the variant is now classified as pathogenic. -

Feb 01, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 14, 2023

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 379319). This missense change has been observed in individuals with autoimmune polyendocrinopathy syndrome (PMID: 18426830, 24158785, 28446514). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 92 of the AIRE protein (p.Arg92Trp). -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AIRE c.274C>T (p.Arg92Trp) variant has been reported in individuals affected with Autoimmune polyendocrine syndrome type I (Ng’weina F et al). The amino acid Arg at position 92 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as pathogenic. The p.Arg92Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg92Trp in AIRE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Apr 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

May 09, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R92W missense variant in the AIRE gene has been reported previously in two compoundheterozygous individals with APS1 (Magitta et al., 2008). R92W was not observed with any significantfrequency in the NHLBI Exome Sequencing Project. In addition, missense variants in nearby residues(L87P, Y90C, L93R, L97P) have been reported in the Human Gene Mutation Database in association with APECED (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Benign

0.13

Eigen_PC

Benign

-0.0098

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.54

MVP

1.0

MPC

0.57

ClinPred

0.99

GERP RS

0.91

Varity_R

0.78

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over