NM_000383.4:c.99T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

autoimmune polyendocrine syndrome type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Myriad Women’s Health, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial isolated hypoparathyroidism due to impaired PTH secretion
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

AIRE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 35669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AIRE	ENST00000291582.6 link	c.99T>C	p.Ala33Ala	synonymous_variant	Exon 1 of 14	1	NM_000383.4	ENSP00000291582.5
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

GnomAD2 exomes

AF:

0.0910

AC:

12890

AN:

141686

AF XY:

0.0847

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 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

African (AFR)

AF:

0.547

AC:

17207

AN:

31480

American (AMR)

AF:

0.0904

AC:

3223

AN:

35654

Ashkenazi Jewish (ASJ)

AF:

0.0767

AC:

1928

AN:

25128

East Asian (EAS)

AF:

0.302

AC:

10757

AN:

35656

South Asian (SAS)

AF:

0.0762

AC:

6035

AN:

79188

European-Finnish (FIN)

AF:

0.0117

AC:

533

AN:

45470

Middle Eastern (MID)

AF:

0.105

AC:

583

AN:

5572

European-Non Finnish (NFE)

AF:

0.0135

AC:

14551

AN:

1078508

Other (OTH)

AF:

0.0764

AC:

4424

AN:

57892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2286

4572

6859

9145

11431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

948

1896

2844

3792

4740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.174

AC:

26482

AN:

152070

Hom.:

5926

Cov.:

AF XY:

0.172

AC XY:

12768

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.512

AC:

21204

AN:

41426

American (AMR)

AF:

0.0968

AC:

1480

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

278

AN:

3470

East Asian (EAS)

AF:

0.305

AC:

1569

AN:

5146

South Asian (SAS)

AF:

0.0799

AC:

386

AN:

4832

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10614

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1095

AN:

67972

Other (OTH)

AF:

0.153

AC:

322

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

753

1506

2260

3013

3766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.4

(source)

DANN

Benign

0.64

PhyloP100

-4.4

PromoterAI

0.024

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over