chr21-44286105-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000383.4(AIRE):c.99T>C(p.Ala33Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0554 in 1,546,618 control chromosomes in the GnomAD database, including 13,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 5926 hom., cov: 32)

Exomes 𝑓: 0.042 ( 7454 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.36

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 21-44286105-T-C is Benign according to our data. Variant chr21-44286105-T-C is described in ClinVar as [Benign]. Clinvar id is 35669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44286105-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.99T>C	p.Ala33Ala	synonymous_variant	Exon 1 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.99T>C	p.Ala33Ala	synonymous_variant	Exon 1 of 14	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 link	n.260T>C		non_coding_transcript_exon_variant	Exon 1 of 14	2
AIRE	ENST00000530812.5 link	n.268T>C		non_coding_transcript_exon_variant	Exon 1 of 12	2

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26395

AN:

151962

Hom.:

5891

Cov.:

show subpopulations

Gnomad AFR

AF:

0.511

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0969

Gnomad ASJ

AF:

0.0801

Gnomad EAS

AF:

0.305

Gnomad SAS

AF:

0.0800

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.148

GnomAD3 exomes

AF:

0.0910

AC:

12890

AN:

141686

Hom.:

1730

AF XY:

0.0847

AC XY:

6508

AN XY:

76840

show subpopulations

Gnomad AFR exome

AF:

0.526

Gnomad AMR exome

AF:

0.0874

Gnomad ASJ exome

AF:

0.0796

Gnomad EAS exome

AF:

0.305

Gnomad SAS exome

AF:

0.0776

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0650

GnomAD4 exome

AF:

0.0425

AC:

59241

AN:

1394548

Hom.:

7454

Cov.:

AF XY:

0.0425

AC XY:

29262

AN XY:

688016

show subpopulations

Gnomad4 AFR exome

AF:

0.547

Gnomad4 AMR exome

AF:

0.0904

Gnomad4 ASJ exome

AF:

0.0767

Gnomad4 EAS exome

AF:

0.302

Gnomad4 SAS exome

AF:

0.0762

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0764

GnomAD4 genome

AF:

0.174

AC:

26482

AN:

152070

Hom.:

5926

Cov.:

AF XY:

0.172

AC XY:

12768

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.512

Gnomad4 AMR

AF:

0.0968

Gnomad4 ASJ

AF:

0.0801

Gnomad4 EAS

AF:

0.305

Gnomad4 SAS

AF:

0.0799

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.153

Alfa

AF:

0.0696

Hom.:

644

Bravo

AF:

0.200

Asia WGS

AF:

0.189

AC:

657

AN:

3456

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polyglandular autoimmune syndrome, type 1

Benign:3

Nov 20, 2010

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.4

DANN

Benign

0.64

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