rs886041293

Variant names:

• chr21-44286139-GTG-CT
• rs886041293
• NM_000383.4:c.132+1_132+3delGTGinsCT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000383.4(AIRE):​c.132+1_132+3delGTGinsCT variant causes a splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIRE NM_000383.4 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.34

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 37, new splice context is: cctGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-44286139-GTG-CT is Pathogenic according to our data. Variant chr21-44286139-GTG-CT is described in ClinVar as [Pathogenic]. Clinvar id is 279973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.132+1_132+3delGTGinsCT		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 13	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.132+1_132+3delGTGinsCT		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 13	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.293+1_293+3delGTGinsCT		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 13	2
AIRE	ENST00000530812.5	n.301+1_301+3delGTGinsCT		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 11	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:2

Jul 03, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.132+1_132+3delinsCT variant in AIRE has been reported in the homozygous or compound heterozygous state in at least 3 individuals with features of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; Stolarski 2006, Capalbo 2008, Gutierrez 2017). It has also been identified in 0.002% (1/50686) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org) and has been reported as Pathogenic in ClinVar (Variation ID 279973). This variant is a deletion of 3 nucleotides and insertion of 2 nucleotides at position c.132+1. This occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the AIRE gene is an established disease mechanism in autosomal recessive APECED. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive APECED. ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2. -

Sep 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as 132+1_132+3delGTGinsCT and IVS1 + 1G > C; IVS1 + 5delG. Disruption of this splice site has been observed in individuals with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) (PMID: 16965330, 18248641, 25554620, 28458664). This sequence change affects a donor splice site in intron 1 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). -

not provided Pathogenic:1

Sep 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16965330, 25554620, 28458664, 18248641) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041293; hg19: chr21-45706022;