chr21-44287085-C-T

Variant names:

• chr21-44287085-C-T
• rs121434256
• NM_000383.4:c.415C>T
• AIRE p.Arg139*

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

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 (★★). The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: AIRE NM_000383.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.259
• Publications: 50 publications found

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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Our verdict: Uncertain_significance. The variant received 1 points.

• O3: Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000006 — very rare (O3 supporting [+1])

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

Sel.	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
	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

Pathogenic	VUS	Benign	Condition
8	-	-	Polyglandular autoimmune syndrome, type 1 (8)
2	-	-	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.

Other links and lift over

dbSNP: rs121434256;

hg19: chr21-45706968;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar