rs886041124

Variant names:

• chr21-44286628-C-CCAGG
• rs886041124
• NM_000383.4:c.205_208dupCAGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000383.4(AIRE):​c.205_208dupCAGG​(p.Asp70AlafsTer148) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AIRE NM_000383.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.10

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-44286628-C-CCAGG is Pathogenic according to our data. Variant chr21-44286628-C-CCAGG is described in ClinVar as [Pathogenic]. Clinvar id is 279674.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.205_208dupCAGG	p.Asp70AlafsTer148	frameshift_variant	Exon 2 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.205_208dupCAGG	p.Asp70AlafsTer148	frameshift_variant	Exon 2 of 14	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.366_369dupCAGG		non_coding_transcript_exon_variant	Exon 2 of 14	2
AIRE	ENST00000530812.5	n.374_377dupCAGG		non_coding_transcript_exon_variant	Exon 2 of 12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460690 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:3

Nov 12, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 07, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: This c.205_208dupCAGG variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 70 and leads to a premature termination codon 148 amino acids downstream. It is predicted to cause a truncated or absent AIRE protein. Loss-of-function due to mutations in this gene is an established disease mechanism in APS1. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg257X, p.Cys311fs). This variant has been reported in multiple APS1 families in homozygous state. However, it was absent in approximately 120132 chromosomes from ExAC. One reputable database has classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic. -

not provided Pathogenic:2

Aug 22, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.205_208dupCAGG variant in the AIRE gene has been reported previously in patients of Arabic ancestry in association with autoimmune polyendocrinopathy syndrome, type 1 (APS1) (Heino et al., 1999; Faiyaz-Ul-Haque et al., 2009). The duplication causes a frameshift starting with codon Aspartic acid 70, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 148 of the new reading frame, denoted p.Asp70AlafsX148. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -

Sep 21, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the AIRE gene demonstrated a four base pair duplication in exon 2, c.205_208dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 147 amino acids downstream of the mutation, p.Asp70Alafs*148. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated AIRE protein with potentially abnormal function. This pathogenic sequence change is not present in large population databases such as gnomAD, and has previously been described in patients with autoimmune polyendocrinopathy syndrome type 1 (PMIDs: 19758376, 9888391). -

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: rs886041124; hg19: chr21-45706511;