21-44285985-CCCGGGTCCCCGCGCCCACCCCATGGCGACGGACGCGGCGCTACG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000383.4(AIRE):c.-17_27del variant causes a start lost, 5 prime UTR change involving the alteration of a non-conserved nucleotide. 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 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.05

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-44285985-CCCGGGTCCCCGCGCCCACCCCATGGCGACGGACGCGGCGCTACG-C is Pathogenic according to our data. Variant chr21-44285985-CCCGGGTCCCCGCGCCCACCCCATGGCGACGGACGCGGCGCTACG-C is described in ClinVar as [Pathogenic]. Clinvar id is 954404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.-17_27del		start_lost, 5_prime_UTR_variant	1/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.-17_27del		start_lost, 5_prime_UTR_variant	1/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.145_188del		non_coding_transcript_exon_variant	1/14	2
AIRE	ENST00000530812.5	n.153_196del		non_coding_transcript_exon_variant	1/12	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 22, 2019

This sequence change affects the initiator methionine of the AIRE mRNA. The next in-frame methionine is located at codon 184. For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in several individuals affected with autoimmune polyendocrinopathy syndrome (PMID: 28911151, 20407228, 19758376, 28446514). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

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: rs2040477031; hg19: chr21-45705868;