21-44294411-C-T

Position:

chr21-44294411-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000383.4(AIRE):c.1411C>T(p.Arg471Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,574,200 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 23 hom., cov: 31)

Exomes 𝑓: 0.013 ( 152 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0790

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:

AIRE (HGNC:):

AIRE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014049828).

BP6

Variant 21-44294411-C-T is Benign according to our data. Variant chr21-44294411-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44294411-C-T is described in Lovd as [Benign]. Variant chr21-44294411-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1686/151696) while in subpopulation NFE AF= 0.0145 (982/67850). AF 95% confidence interval is 0.0137. There are 23 homozygotes in gnomad4. There are 921 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4 linkuse as main transcript	c.1411C>T	p.Arg471Cys	missense_variant	12/14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6 linkuse as main transcript	c.1411C>T	p.Arg471Cys	missense_variant	12/14	1	NM_000383.4	ENSP00000291582.5		O43918-1

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1683

AN:

151580

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00544

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.0457

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0145

Gnomad OTH

AF:

0.00962

GnomAD3 exomes

AF:

0.00924

AC:

1743

AN:

188644

Hom.:

AF XY:

0.00924

AC XY:

964

AN XY:

104298

show subpopulations

Gnomad AFR exome

AF:

0.00158

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.00549

Gnomad EAS exome

AF:

0.000129

Gnomad SAS exome

AF:

0.000733

Gnomad FIN exome

AF:

0.0377

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.00758

GnomAD4 exome

AF:

0.0129

AC:

18420

AN:

1422504

Hom.:

152

Cov.:

AF XY:

0.0125

AC XY:

8841

AN XY:

705756

show subpopulations

Gnomad4 AFR exome

AF:

0.00154

Gnomad4 AMR exome

AF:

0.00357

Gnomad4 ASJ exome

AF:

0.00502

Gnomad4 EAS exome

AF:

0.000233

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.0366

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.00930

GnomAD4 genome

AF:

0.0111

AC:

1686

AN:

151696

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

921

AN XY:

74118

show subpopulations

Gnomad4 AFR

AF:

0.00242

Gnomad4 AMR

AF:

0.00544

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000417

Gnomad4 FIN

AF:

0.0457

Gnomad4 NFE

AF:

0.0145

Gnomad4 OTH

AF:

0.00951

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.00775

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00249

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00849

AC:

994

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28911151, 26650942, 20718774, 25402387, 24014553, 21070315, 19863576) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	AIRE: BS1, BS2 -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2021	Variant summary: AIRE c.1411C>T (p.Arg471Cys) results in a non-conservative amino acid change located in the PHD-type Zinc finger domain (IPR001965) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.01 in 333270 control chromosomes, predominantly at a frequency of 0.014 within the European subpopulation in the gnomAD database (v2.1, v3, and publication data), including 19 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (APS-1) phenotype (0.0028), strongly suggesting that the variant is a benign polymorphism. The variant, c.1411C>T, has been reported in homozygosity in 3 patients affected with isolated primary adrenal insufficiency (Betterle_2013, Tsai_2016), and in compound heterozygous state with a loss of function AIRE variant in an individual affected with isolated primary hypoparathyroidism (Orlova_2017), however, the three major components of APS-1 were not present in these patients, and the lack of characteristic autoantibodies present in APS-1 was also noted in several cases. On the other hand, the variant has also been reported in the literature in heterozygous state in patients with isolated adrenal insufficiency (Boe Wolff_2008, Orlova_2010), isolated hypoparathyroidism (Cervato_2010), and adrenal insufficiency with type 1 diabetes and/or autoimmune thyroid disease, i.e. with autoimmune polyglandular syndrome type 2 (APS-2) (Toth_2010, Resende_2014). Recent large scale genome-wide association studies (GWAS) demonstrated that the p.R471C (rs74203920) variant was enriched in patients affected with isolated autoimmune Addison's disease (AAD) and APS-2 (OR = 3.4) (Eriksson_2021), and also in patients affected with (isolated) type 1 diabetes (Chiou_2021), although the effect of linkage disequilibrium with nearby genes/variants cannot be excluded. Two publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the R471C variant had no significant effect on the expression of AIRE-dependent genes, neither in co-transfection experiments with the wild-type gene, nor when the variant was transfected alone (Oftedal_2015, Eriksson_2021). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign/likely benign. In conclusion, current evidence does not support the variant as a cause of APS-1, but instead points to an increased risk of isolated- or multi-organ autoimmune endocrine diseases at the population level. Therefore, based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 08, 2021	- -

Polyglandular autoimmune syndrome, type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 02, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.054

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.57

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.75

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.56

Sift

Benign

0.033

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.36

MVP

0.98

MPC

0.16

ClinPred

0.0093

GERP RS

2.7

Varity_R

0.13

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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