21-44287085-C-G

Variant names:

• chr21-44287085-C-G
• rs121434256
• NM_000383.4:c.415C>G
• AIRE p.Arg139Gly

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-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). B3_Supporting

The NM_000383.4(AIRE):c.415C>G (p.Arg139Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000254 (AC=41) in the gnomAD database across 1,612,098 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000299. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R139P: Uncertain_significance (ClinVar VariationId 1449867, 1 star)

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -1 points.

• B3: Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

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>G	p.Arg139Gly	missense	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>G	p.Arg139Gly	missense	Exon 3 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.415C>G	p.Arg139Gly	missense	Exon 3 of 14	ENSP00000636237.1	A0ACI8VCZ1
	AIRE	ENST00000527919.5	TSL:2	n.576C>G		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: 0.000131	AC:20	Hom:0	AN:152102	Cov:32
GnomAD2 exomes	AF: 0.0000455	AC:11	Hom:	AN:242012	Cov:
GnomAD4 exome	AF: 0.0000144	AC:21	Hom:0	AN:1459996	Cov:32
GnomAD4 genome	AF: 0.000131	AC:20	Hom:0	AN:152102	Cov:32
TOPMed (Bravo)	AF: 0.000174	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000349	AC:1	Hom:0	AN:286684	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000449	3	66888
SCHEMA(Schizophrenia)	0.0000531	6	113054	0.0000735	14	190426

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Uncertain	-	15
AlphaMissense	Benign	-	0.090
BayesDel_addAF	Benign	T	-0.20
BayesDel_noAF	Benign	-	-0.14
CADD	Benign	-	17
DANN	Benign	-	0.84
DEOGEN2	Benign	T	0.39
Eigen	Benign	-	-0.33
Eigen_PC	Benign	-	-0.59
FATHMM_MKL	Benign	N	0.0046
FuncVEP CTI	Benign	-	0.023
GPN-Star LLR	N/A	-	-4.3
GPN-Star score	N/A	-	4.3
LIST_S2	Benign	T	0.55
M_CAP	Uncertain	D	0.13
MetaRNN	Benign	T	0.20
MetaSVM	Uncertain	D	0.17
Mutation Taster	N/A	polymorphism	94/6
MutationAssessor	Uncertain	M	2.1
PhyloP100	Benign	-	0.26
popEVE	Benign	-	-2.7
PrimateAI	Uncertain	T	0.62
PROVEAN	Uncertain	D	-2.9
REVEL	Benign	-	0.28
Sift	Benign	T	0.45
Sift4G	Benign	T	0.60
Varity_R	N/A	-	0.11
VESM-3B	Benign	-	-2.4

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.020
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 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