chr21-44297667-T-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.1578T>C(p.Asp526Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,611,030 control chromosomes in the GnomAD database, including 155,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19394 hom., cov: 33)

Exomes 𝑓: 0.43 ( 135917 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.97

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=-0.72).

BP6

Variant 21-44297667-T-C is Benign according to our data. Variant chr21-44297667-T-C is described in ClinVar as Benign. ClinVar VariationId is 128337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000383.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.1578T>C	p.Asp526Asp	synonymous	Exon 14 of 14	NP_000374.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1578T>C	p.Asp526Asp	synonymous	Exon 14 of 14	ENSP00000291582.5
AIRE	ENST00000337909.5	TSL:1	n.1039T>C		non_coding_transcript_exon	Exon 7 of 7
AIRE	ENST00000397994.8	TSL:5	n.957T>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes

AF:

0.492

AC:

74726

AN:

151966

Hom.:

19354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.647

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.667

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.410

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.466

GnomAD2 exomes

AF:

0.459

AC:

114178

AN:

248750

AF XY:

0.450

show subpopulations

Gnomad AFR exome

AF:

0.652

Gnomad AMR exome

AF:

0.506

Gnomad ASJ exome

AF:

0.446

Gnomad EAS exome

AF:

0.659

Gnomad FIN exome

AF:

0.406

Gnomad NFE exome

AF:

0.409

Gnomad OTH exome

AF:

0.438

GnomAD4 exome

AF:

0.428

AC:

623919

AN:

1458944

Hom.:

135917

Cov.:

AF XY:

0.426

AC XY:

308893

AN XY:

725868

show subpopulations

African (AFR)

AF:

0.657

AC:

21986

AN:

33452

American (AMR)

AF:

0.499

AC:

22314

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

11595

AN:

26132

East Asian (EAS)

AF:

0.653

AC:

25930

AN:

39682

South Asian (SAS)

AF:

0.416

AC:

35874

AN:

86236

European-Finnish (FIN)

AF:

0.406

AC:

20984

AN:

51638

Middle Eastern (MID)

AF:

0.493

AC:

2838

AN:

5760

European-Non Finnish (NFE)

AF:

0.410

AC:

455470

AN:

1110994

Other (OTH)

AF:

0.446

AC:

26928

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

19321

38642

57963

77284

96605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14418

28836

43254

57672

72090

<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:

0.492

AC:

74819

AN:

152086

Hom.:

19394

Cov.:

AF XY:

0.494

AC XY:

36738

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.647

AC:

26840

AN:

41492

American (AMR)

AF:

0.497

AC:

7609

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1578

AN:

3470

East Asian (EAS)

AF:

0.667

AC:

3444

AN:

5162

South Asian (SAS)

AF:

0.428

AC:

2061

AN:

4816

European-Finnish (FIN)

AF:

0.410

AC:

4345

AN:

10588

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.404

AC:

27455

AN:

67950

Other (OTH)

AF:

0.470

AC:

989

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1862

3724

5587

7449

9311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.441

Hom.:

20341

Bravo

AF:

0.505

Asia WGS

AF:

0.509

AC:

1775

AN:

3478

EpiCase

AF:

0.418

EpiControl

AF:

0.412

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported.

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.

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

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

Polyglandular autoimmune syndrome, type 1

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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:2

Mar 03, 2015

GeneDx

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.098

(source)

DANN

Benign

0.65

PhyloP100

-2.0

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over