rs199612115

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_ModeratePP5

The NM_000383.4(AIRE):c.652+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000226 in 1,592,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

AIRE
NM_000383.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 4.80

Publications

3 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: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06959707 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP5

Variant 21-44288459-G-T is Pathogenic according to our data. Variant chr21-44288459-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 370839.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.652+1G>T		splice_donor_variant, intron_variant	Intron 5 of 13	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
AIRE	ENST00000291582.6 link	c.652+1G>T	splice_donor_variant, intron_variant	Intron 5 of 13	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000530812.5 link	n.1205G>T	non_coding_transcript_exon_variant	Exon 4 of 12	2
AIRE	ENST00000527919.5 link	n.1196+1G>T	splice_donor_variant, intron_variant	Intron 4 of 13	2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000964

AC:

AN:

248874

AF XY:

0.0000889

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000181

AC:

AN:

1439672

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

717230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33040

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.000581

AC:

AN:

39574

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092778

Other (OTH)

AF:

0.0000335

AC:

AN:

59664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00173

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.0000626

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000577

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1

Pathogenic:5

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 5 of the AIRE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs199612115, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. ClinVar contains an entry for this variant (Variation ID: 370839). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Apr 22, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 13, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AIRE-related disorder

Pathogenic:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The AIRE c.652+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in three unaffected individuals who were part of a carrier study of autosomal recessive inherited disorders (Chau et al. 2022. PubMed ID: 35314707). This variant was reported in an individual with Autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (Chau et al 2022. PubMed ID: 35314707; Heino M et al 2001. PubMed ID: 11524731; Placeholder for https://www.ncbi.nlm.nih.gov/pmc/?term=4544753 ; Kisand K et al 2015. PubMed ID: 26141571; Baralle D et al 2005. PubMed ID: 16199547). This variant is reported in 0.13% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-45708342-G-T). Variants that disrupt the consensus splice donor site in AIRE are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided

Uncertain:1

Nov 15, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified as a single heterozygous variant in patients in published literature, but additional evidence is not available (PMID: 35314707); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35314707) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.85

PhyloP100

4.8

GERP RS

3.6

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.95

Position offset: -1

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