rs121434258

chr21-44286007-A-Gchr21-44286007-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000383.4(AIRE):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,529,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: AIRE NM_000383.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -1.01

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000383.4 (AIRE) was described as [Pathogenic] in ClinVar as 3314
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-44286007-A-G is Pathogenic according to our data. Variant chr21-44286007-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44286007-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.1A>G	p.Met1?	start_lost	1/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.1A>G	p.Met1?	start_lost	1/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.162A>G		non_coding_transcript_exon_variant	1/14	2
AIRE	ENST00000530812.5	n.170A>G		non_coding_transcript_exon_variant	1/12	2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151882 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000777 AC: 1 AN: 128782 Hom.: 0 AF XY: 0.0000142 AC XY: 1 AN XY: 70650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000449

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1378002 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 679800

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: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151990 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000147 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 21, 2021	For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 19758376, 28446514, 28911151,16965330). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551136). While this variant is present in population databases (rs121434258), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change affects the initiator methionine of the AIRE mRNA. The next in-frame methionine is located at codon 184. -

Inherited Immunodeficiency Diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	3.4
Dann	Benign	0.53
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.49
Sift	Benign	0.087	T
Sift4G	Uncertain	0.048	D
Polyphen		0.0	B
Vest4		0.63
MutPred		0.88		Loss of helix (P = 0.0626);
MVP		0.89
ClinPred		0.042	T
GERP RS		-1.9
Varity_R		0.13
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121434258; hg19: chr21-45705890;