Variant chr21-44292371-C-T details in Genebe, Genetics Data Aggregator

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.1065C>T(p.Pro355Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,562,830 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.412

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 21-44292371-C-T is Benign according to our data. Variant chr21-44292371-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 528312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44292371-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.412 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 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/exons	MANE	Protein	UniProt
AIRE	NM_000383.4 linkuse as main transcript	c.1065C>T	p.Pro355Pro	synonymous_variant	9/14	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.1065C>T	p.Pro355Pro	synonymous_variant	9/14	1	NM_000383.4	ENSP00000291582.5		O43918-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00278

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00127

AC:

207

AN:

163372

Hom.:

AF XY:

0.00128

AC XY:

112

AN XY:

87392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000808

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00235

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.00133

AC:

1878

AN:

1410674

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

945

AN XY:

696812

show subpopulations

Gnomad4 AFR exome

AF:

0.000185

Gnomad4 AMR exome

AF:

0.000696

Gnomad4 ASJ exome

AF:

0.000119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00188

Gnomad4 NFE exome

AF:

0.00157

Gnomad4 OTH exome

AF:

0.000839

GnomAD4 genome

AF:

0.00175

AC:

267

AN:

152156

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00278

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AIRE: BP4, BP7 -

Polyglandular autoimmune syndrome, type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 26, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.6

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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