Genetic Variant AIRE:p.Pro166Gln (chr21-44287550-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000383.4(AIRE):c.497C>A(p.Pro166Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P166L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0940

Publications

0 publications found

Variant links:

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, PanelApp Australia, Ambry Genetics, Myriad Women’s Health, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
familial isolated hypoparathyroidism due to impaired PTH secretion
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

AIRE links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23787206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.497C>A	p.Pro166Gln	missense_variant	Exon 4 of 14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AIRE	ENST00000291582.6 link	c.497C>A	p.Pro166Gln	missense_variant	Exon 4 of 14	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 link	n.1041C>A		non_coding_transcript_exon_variant	Exon 3 of 14	2
AIRE	ENST00000530812.5 link	n.1049C>A		non_coding_transcript_exon_variant	Exon 3 of 12	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1406990

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694682

show subpopulations

African (AFR)

AF:

0.0000310

AC:

AN:

32218

American (AMR)

AF:

0.00

AC:

AN:

36770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25236

East Asian (EAS)

AF:

0.00

AC:

AN:

36906

South Asian (SAS)

AF:

0.00

AC:

AN:

79784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083678

Other (OTH)

AF:

0.00

AC:

AN:

58308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

0.0018

BayesDel_noAF

Benign

-0.24

CADD

Benign

4.3

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.53

M_CAP

Benign

0.076

MetaRNN

Benign

0.24

MetaSVM

Uncertain

0.040

MutationAssessor

Benign

2.0

PhyloP100

-0.094

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.26

Sift

Benign

0.058

Sift4G

Benign

0.065

Polyphen

0.90

Vest4

0.071

MutPred

0.21

Loss of glycosylation at P166 (P = 0.0166);

MVP

0.99

MPC

0.12

ClinPred

0.59

GERP RS

1.4

Varity_R

0.071

gMVP

0.22

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over