rs1162316051

Positions:

• chr21-44286994-GC-G

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.328del​(p.Arg110GlyfsTer37) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AIRE NM_000383.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.802

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-44286994-GC-G is Pathogenic according to our data. Variant chr21-44286994-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.328del	p.Arg110GlyfsTer37	frameshift_variant	3/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.328del	p.Arg110GlyfsTer37	frameshift_variant	3/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.489del		non_coding_transcript_exon_variant	3/14	2
AIRE	ENST00000530812.5	n.497del		non_coding_transcript_exon_variant	3/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245766 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460482 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2023	This sequence change creates a premature translational stop signal (p.Arg110Glyfs*37) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autoimmune polyendocrinopathy syndrome (PMID: 24948345). ClinVar contains an entry for this variant (Variation ID: 553161). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Sep 14, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Jun 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1162316051; hg19: chr21-45706877;