21-44287085-C-T

Variant names:

Variant summary

Our verdict is The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_000383.4(AIRE):c.415C>T (p.Arg139*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000112 (AC=18) in the gnomAD database across 1,612,216 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000576. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

AIRE
NM_000383.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.259

Publications

50 publications found

Variant links:

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]

AIRE Gene-Disease associations (from GenCC):

autoimmune polyendocrine syndrome type 1
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Natera, Myriad Women's Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp, PanelApp Australia
familial isolated hypoparathyroidism due to impaired PTH secretion
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

AIRE links:

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new If you want to explore the variant's impact on the transcript NM_000383.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 points.

PVS1

Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 3 of 14) at amino acid 139 of 545, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.

PM2

Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000576 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00103) — PM2 moderate.

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (10/10 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000383.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.415C>T	p.Arg139*	stop_gained	Exon 3 of 14	NP_000374.1	O43918-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIRE	ENST00000291582.6	TSL:1 MANE Select	c.415C>T	p.Arg139*	stop_gained	Exon 3 of 14	ENSP00000291582.5	O43918-1
AIRE	ENST00000966178.1		c.415C>T	p.Arg139*	stop_gained	Exon 3 of 14	ENSP00000636237.1	A0ACI8VCZ1
AIRE	ENST00000527919.5	TSL:2	n.576C>T		non_coding_transcript_exon	Exon 3 of 14

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152102	Cov:32
GnomAD2 exomes	AF: 0.0000248	AC:6	Hom:	AN:242012	Cov:
GnomAD4 exome	AF: 0.00000959	AC:14	Hom:0	AN:1459996	Cov:32
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152220	Cov:32
TOPMed (Bravo)	AF: 0.0000378	AC:10	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000244	AC:7	Hom:0	AN:286684	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
Cohort	AF	AC	AN	AF	AC	AN
BipEx (Bipolar disorder (including schizoaffective))	0.00	0	28418	0.0000347	1	28844
Epi25 (Epilepsy)	0.00	0	41958	0.0000299	2	66888
SCHEMA (Schizophrenia)	0.0000129	1	77620	0.0000216	3	139188

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Polyglandular autoimmune syndrome, type 1 (8)

not provided (2)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	33
BayesDel_addAF	Pathogenic	D	0.49
BayesDel_noAF	Pathogenic	-	0.20
CADD	Pathogenic	-	35
DANN	Uncertain	-	0.99
Eigen	Benign	-	-0.092
Eigen_PC	Benign	-	-0.47
FATHMM_MKL	Benign	N	0.076
GPN-Star LLR	N/A	-	-7.1
GPN-Star score	N/A	-	7.1
Mutation Taster	N/A	disease causing (ClinVar)	2/198
PhyloP100	Benign	-	0.26

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.14
Pangolin loss	Benign	- Position offset: 48	0.14
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.11

Showing 3 of 3 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Case/control cohorts

ClinVar

Computational Scores

Splicing Scores

Publications

Other links and lift over