chr21-44286049-C-T

Variant names:

• chr21-44286049-C-T
• rs179363875
• NM_000383.4:c.43C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000383.4(AIRE):​c.43C>T​(p.Arg15Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,387,712 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 0.830
• Publications: 4 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 12 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000383.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-44286049-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1481156.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 21-44286049-C-T is Pathogenic according to our data. Variant chr21-44286049-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 68225.Status of the report is criteria_provided_single_submitter, 1 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.43C>T	p.Arg15Cys	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.43C>T	p.Arg15Cys	missense	Exon 1 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.43C>T	p.Arg15Cys	missense	Exon 1 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.204C>T		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1387712 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 684678

African (AFR) AF: 0.00 AC: 0 AN: 31496

American (AMR) AF: 0.00 AC: 0 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.0000841 AC: 3 AN: 35662

South Asian (SAS) AF: 0.00 AC: 0 AN: 79148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5372

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077876

Other (OTH) AF: 0.00 AC: 0 AN: 57776

GnomAD4 genome Cov.: 33

Alfa AF: 0.00280 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Polyglandular autoimmune syndrome, type 1 (2)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.83
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.94		Loss of MoRF binding (P = 0.0032)
MVP		0.99
MPC		0.65
ClinPred		1.0	D
GERP RS		3.8
PromoterAI		0.0047	Neutral
Varity_R		0.93
gMVP		0.88
Mutation Taster		=17/83	disease causing

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: rs179363875; hg19: chr21-45705932;