21-44293832-C-T

Position:

chr21-44293832-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000383.4(AIRE):c.1322C>T(p.Thr441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,596,942 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2O:1

Conservation

PhyloP100: -0.620

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.116511256).

BP6

Variant 21-44293832-C-T is Benign according to our data. Variant chr21-44293832-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35660.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=1, not_provided=1, Benign=1}. Variant chr21-44293832-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.1322C>T	p.Thr441Met	missense_variant	11/14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6 link	c.1322C>T	p.Thr441Met	missense_variant	11/14	1	NM_000383.4	ENSP00000291582.5		O43918-1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00147

AC:

351

AN:

238236

Hom.:

AF XY:

0.00159

AC XY:

207

AN XY:

130298

show subpopulations

Gnomad AFR exome

AF:

0.000315

Gnomad AMR exome

AF:

0.000610

Gnomad ASJ exome

AF:

0.00362

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.000167

Gnomad NFE exome

AF:

0.00173

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.00165

AC:

2389

AN:

1444798

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

1193

AN XY:

719206

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00262

Gnomad4 FIN exome

AF:

0.000158

Gnomad4 NFE exome

AF:

0.00169

Gnomad4 OTH exome

AF:

0.00221

GnomAD4 genome

AF:

0.00103

AC:

156

AN:

152144

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.000975

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00130

AC:

157

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1

Uncertain:3Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 09, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 01-09-2019 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Sep 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	AIRE: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported previously in a female patient with systemic sclerosis associated with autoimmune thyroiditis and Sjogren syndrome who had no features of autoimmune polyendocrinopathy syndrome (Ferrera et al., 2007), and in a patient with primary immunodeficiency disease who also harbored variants in other genes (Chi et al., 2018); This variant is associated with the following publications: (PMID: 30290665, 27266815, 17101293) -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2023	Variant summary: AIRE c.1322C>T (p.Thr441Met) results in a non-conservative amino acid change located in the Zinc finger, PHD-type domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 269480 control chromosomes, including one homozygote, predominantly at a frequency of 0.0035 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), while, the frequency within South Asian control individuals is equal to the estimated maximal expected allele frequency for a pathogenic variant; these data suggesting that the variant is a benign polymorphism. c.1322C>T has been reported in the literature in individuals affected with Addison disease, primary immunodeficiency disease and autoimmune thyroiditis, Sjogren syndrome and mendelian susceptibility to mycobacterial diseases (Chi_2018, Ferrera_2007, Mazza_unpublished abstract_2006. Suratannon_2020). These reports do not provide unequivocal conclusions about association of the variant with Autoimmune Polyglandular Syndrome Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17101293, No_PMID, 30290665, 32373116). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.57

Sift

Benign

0.078

Sift4G

Benign

0.085

Polyphen

0.97

Vest4

0.73

MVP

0.97

MPC

0.25

ClinPred

0.013

GERP RS

0.63

Varity_R

0.038

gMVP

0.31

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