21-44289685-C-T

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.681C>T(p.Gly227Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,612,616 control chromosomes in the GnomAD database, including 57,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G227G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.20 ( 4060 hom., cov: 33)

Exomes 𝑓: 0.26 ( 53911 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -2.24

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=-0.57).

BP6

Variant 21-44289685-C-T is Benign according to our data. Variant chr21-44289685-C-T is described in ClinVar as Benign. ClinVar VariationId is 128339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.681C>T	p.Gly227Gly	synonymous_variant	Exon 6 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.681C>T	p.Gly227Gly	synonymous_variant	Exon 6 of 14	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 link	n.1414C>T		non_coding_transcript_exon_variant	Exon 6 of 14	2
AIRE	ENST00000530812.5 link	n.2431C>T		non_coding_transcript_exon_variant	Exon 4 of 12	2

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30502

AN:

152040

Hom.:

4057

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0542

Gnomad AMI

AF:

0.303

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.202

GnomAD2 exomes

AF:

0.226

AC:

56380

AN:

249922

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.0479

Gnomad AMR exome

AF:

0.243

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.00501

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.282

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.263

AC:

384500

AN:

1460458

Hom.:

53911

Cov.:

AF XY:

0.261

AC XY:

189649

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.0431

AC:

1444

AN:

33480

American (AMR)

AF:

0.241

AC:

10761

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

4880

AN:

26120

East Asian (EAS)

AF:

0.00524

AC:

208

AN:

39700

South Asian (SAS)

AF:

0.175

AC:

15111

AN:

86258

European-Finnish (FIN)

AF:

0.316

AC:

16447

AN:

52114

Middle Eastern (MID)

AF:

0.130

AC:

750

AN:

5768

European-Non Finnish (NFE)

AF:

0.289

AC:

321118

AN:

1111930

Other (OTH)

AF:

0.228

AC:

13781

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

17800

35600

53400

71200

89000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10320

20640

30960

41280

51600

<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:

0.201

AC:

30510

AN:

152158

Hom.:

4060

Cov.:

AF XY:

0.199

AC XY:

14821

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0540

AC:

2245

AN:

41550

American (AMR)

AF:

0.198

AC:

3029

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

663

AN:

3470

East Asian (EAS)

AF:

0.00367

AC:

AN:

5182

South Asian (SAS)

AF:

0.169

AC:

814

AN:

4822

European-Finnish (FIN)

AF:

0.328

AC:

3467

AN:

10586

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.287

AC:

19532

AN:

67942

Other (OTH)

AF:

0.199

AC:

419

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1181

2361

3542

4722

5903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.240

Hom.:

7591

Bravo

AF:

0.185

Asia WGS

AF:

0.0720

AC:

248

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.265

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Polyglandular autoimmune syndrome, type 1

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2019

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

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Mar 03, 2015

GeneDx

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

-0.57

CADD

Benign

0.90

(source)

DANN

Benign

0.57

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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