NM_000383.4:c.47C>G

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000383.4(AIRE):​c.47C>G​(p.Thr16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T16M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain HSR (size 104) in uniprot entity AIRE_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) 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 chr21-44286053-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 21-44286053-C-G is Pathogenic according to our data. Variant chr21-44286053-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3251578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44286053-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.47C>G	p.Thr16Arg	missense_variant	Exon 1 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.47C>G	p.Thr16Arg	missense_variant	Exon 1 of 14	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.208C>G		non_coding_transcript_exon_variant	Exon 1 of 14	2
AIRE	ENST00000530812.5	n.216C>G		non_coding_transcript_exon_variant	Exon 1 of 12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388486 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 685104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Pathogenic:2

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AIRE c.47C>G (p.Thr16Arg) results in a non-conservative amino acid change located in the HSR domain (IPR004865) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent from 135998 control chromosomes. c.47C>G has been reported in the literature in at least one homozygous individual affected with Autoimmune Polyglandular Syndrome Type 1 (e.g. Yan_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant located at the same codon (c.347C>T, p.Thr16Met) has been classified as pathogenic, supporting a critical relevance of this residue to AIRE protein function. The following publication has been ascertained in the context of this evaluation (PMID: 32358377). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.76		Loss of sheet (P = 0.007);
MVP		0.99
MPC		0.60
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.92
gMVP		0.96

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45705936;