rs1800521

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.1197T>C(p.Ala399Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,609,302 control chromosomes in the GnomAD database, including 109,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12115 hom., cov: 33)

Exomes 𝑓: 0.36 ( 96930 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.0500

Publications

23 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=-0.96).

BP6

Variant 21-44293094-T-C is Benign according to our data. Variant chr21-44293094-T-C is described in ClinVar as Benign. ClinVar VariationId is 128336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.1197T>C	p.Ala399Ala	synonymous_variant	Exon 10 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.1197T>C	p.Ala399Ala	synonymous_variant	Exon 10 of 14	1	NM_000383.4	ENSP00000291582.5		O43918-1

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59434

AN:

151888

Hom.:

12099

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.368

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.365

GnomAD2 exomes

AF:

0.350

AC:

84601

AN:

241844

AF XY:

0.349

show subpopulations

Gnomad AFR exome

AF:

0.493

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.417

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.358

GnomAD4 exome

AF:

0.363

AC:

529004

AN:

1457294

Hom.:

96930

Cov.:

AF XY:

0.361

AC XY:

261661

AN XY:

724716

show subpopulations

African (AFR)

AF:

0.497

AC:

16600

AN:

33430

American (AMR)

AF:

0.297

AC:

13143

AN:

44322

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

9607

AN:

25962

East Asian (EAS)

AF:

0.282

AC:

11163

AN:

39572

South Asian (SAS)

AF:

0.306

AC:

26284

AN:

85898

European-Finnish (FIN)

AF:

0.416

AC:

21482

AN:

51680

Middle Eastern (MID)

AF:

0.387

AC:

2195

AN:

5672

European-Non Finnish (NFE)

AF:

0.366

AC:

406230

AN:

1110618

Other (OTH)

AF:

0.371

AC:

22300

AN:

60140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

19510

39021

58531

78042

97552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12998

25996

38994

51992

64990

<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:

0.391

AC:

59484

AN:

152008

Hom.:

12115

Cov.:

AF XY:

0.392

AC XY:

29095

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.488

AC:

20238

AN:

41448

American (AMR)

AF:

0.352

AC:

5373

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.368

AC:

1278

AN:

3470

East Asian (EAS)

AF:

0.257

AC:

1326

AN:

5160

South Asian (SAS)

AF:

0.297

AC:

1435

AN:

4826

European-Finnish (FIN)

AF:

0.418

AC:

4433

AN:

10594

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.357

AC:

24227

AN:

67918

Other (OTH)

AF:

0.363

AC:

763

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1895

3789

5684

7578

9473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

566

1132

1698

2264

2830

<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:

0.366

Hom.:

5433

Bravo

AF:

0.388

Asia WGS

AF:

0.267

AC:

931

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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. -

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

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polyglandular autoimmune syndrome, type 1

Benign:3

Jul 10, 2021

Genome-Nilou Lab

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

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

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. 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. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

2.6

(source)

DANN

Benign

0.43

PhyloP100

0.050

Mutation Taster

=88/12

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