NM_000383.4:c.1083C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBP6_ModerateBP7BS2_Supporting

The NM_000383.4(AIRE):c.1083C>T(p.Pro361Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,554,128 control chromosomes in the GnomAD database, including 3 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. P361P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 3 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -6.80

Publications

0 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 21-44292389-C-T is Benign according to our data. Variant chr21-44292389-C-T is described in ClinVar as Benign. ClinVar VariationId is 458612.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-6.8 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.1083C>T	p.Pro361Pro	synonymous_variant	Exon 9 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.1083C>T	p.Pro361Pro	synonymous_variant	Exon 9 of 14	1	NM_000383.4	ENSP00000291582.5		O43918-1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

162

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00353

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000348

AC:

AN:

152428

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.000280

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000253

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.000158

AC:

222

AN:

1401976

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

691878

show subpopulations

African (AFR)

AF:

0.00431

AC:

138

AN:

32048

American (AMR)

AF:

0.000413

AC:

AN:

36312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25188

East Asian (EAS)

AF:

0.000191

AC:

AN:

36568

South Asian (SAS)

AF:

0.0000629

AC:

AN:

79534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48066

Middle Eastern (MID)

AF:

0.000566

AC:

AN:

5298

European-Non Finnish (NFE)

AF:

0.0000287

AC:

AN:

1080900

Other (OTH)

AF:

0.000396

AC:

AN:

58062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00106

AC:

161

AN:

152152

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00349

AC:

145

AN:

41520

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67944

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000426

Hom.:

Bravo

AF:

0.00139

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AIRE-related disorder

Benign:1

Jan 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.095

(source)

DANN

Benign

0.78

PhyloP100

-6.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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