21-44286053-C-T

Variant names:

• chr21-44286053-C-T
• rs179363877
• NM_000383.4:c.47C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000383.4(AIRE):​c.47C>T​(p.Thr16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000072 in 1,388,486 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001201288: Experimental studies have shown that this missense change affects AIRE function (PMID:14974083)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T16R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.30
• Publications: 20 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 Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001201288: Experimental studies have shown that this missense change affects AIRE function (PMID: 14974083).; SCV005364453: An in vitro experimental study suggests this variant disrupts the homomultimerization of the protein (Figure 5, Halonen et al. 2004. PubMed ID: 14974083).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000383.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-44286053-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3251578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 21-44286053-C-T is Pathogenic according to our data. Variant chr21-44286053-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 68227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.47C>T	p.Thr16Met	missense	Exon 1 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.47C>T	p.Thr16Met	missense	Exon 1 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.47C>T	p.Thr16Met	missense	Exon 1 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.208C>T		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000720 AC: 10 AN: 1388486 Hom.: 0 Cov.: 30 AF XY: 0.00000584 AC XY: 4 AN XY: 685104

African (AFR) AF: 0.00 AC: 0 AN: 31506

American (AMR) AF: 0.00 AC: 0 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 35664

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5434

European-Non Finnish (NFE) AF: 0.00000835 AC: 9 AN: 1077854

Other (OTH) AF: 0.00 AC: 0 AN: 57800

GnomAD4 genome Cov.: 33

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Polyglandular autoimmune syndrome, type 1 (5)
1	-	-	AIRE-related disorder (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.83		Loss of sheet (P = 0.0315)
MVP		0.99
MPC		0.57
ClinPred		0.99	D
GERP RS		3.8
PromoterAI		-0.038	Neutral
Varity_R		0.36
gMVP		0.87
Mutation Taster		=57/43	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs179363877; hg19: chr21-45705936; COSMIC: COSV52394420; COSMIC: COSV52394420;