21-44294476-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_Very_StrongBP7BS2_Supporting

The NM_000383.4(AIRE):c.1476C>T(p.Pro492Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,542,820 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P492P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.58

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 21-44294476-C-T is Benign according to our data. Variant chr21-44294476-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44294476-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.58 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.1476C>T	p.Pro492Pro	synonymous_variant	Exon 12 of 14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6 link	c.1476C>T	p.Pro492Pro	synonymous_variant	Exon 12 of 14	1	NM_000383.4	ENSP00000291582.5		O43918-1

Frequencies

GnomAD3 genomes

AF:

0.000890

AC:

135

AN:

151734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000436

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00158

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000952

AC:

144

AN:

151250

Hom.:

AF XY:

0.000929

AC XY:

AN XY:

83928

show subpopulations

Gnomad AFR exome

AF:

0.000344

Gnomad AMR exome

AF:

0.000199

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000445

Gnomad FIN exome

AF:

0.000592

Gnomad NFE exome

AF:

0.00202

Gnomad OTH exome

AF:

0.000486

GnomAD4 exome

AF:

0.00167

AC:

2325

AN:

1390970

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1135

AN XY:

687906

show subpopulations

Gnomad4 AFR exome

AF:

0.000279

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.0000409

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000507

Gnomad4 FIN exome

AF:

0.000593

Gnomad4 NFE exome

AF:

0.00207

Gnomad4 OTH exome

AF:

0.000847

GnomAD4 genome

AF:

0.000889

AC:

135

AN:

151850

Hom.:

Cov.:

AF XY:

0.000916

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.000435

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00158

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000428

Hom.:

Bravo

AF:

0.000914

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 07, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18200029) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AIRE: BP4, BP7 -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polyglandular autoimmune syndrome, type 1

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.15

DANN

Benign

0.73

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