dbSNP rs1231469574: AIRE:p.Arg8Ser (chr21-44286028-C-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000383.4(AIRE):c.22C>A(p.Arg8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R8C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.838

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 10 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 chr21-44286028-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552873.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.22C>A	p.Arg8Ser	missense_variant	Exon 1 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.22C>A	p.Arg8Ser	missense_variant	Exon 1 of 14	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 link	n.183C>A		non_coding_transcript_exon_variant	Exon 1 of 14	2
AIRE	ENST00000530812.5 link	n.191C>A		non_coding_transcript_exon_variant	Exon 1 of 12	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1382642

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31382

American (AMR)

AF:

0.00

AC:

AN:

35574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25028

East Asian (EAS)

AF:

0.00

AC:

AN:

35570

South Asian (SAS)

AF:

0.00

AC:

AN:

79052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4936

European-Non Finnish (NFE)

AF:

9.29e-7

AC:

AN:

1076978

Other (OTH)

AF:

0.00

AC:

AN:

57608

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.091

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.2

PhyloP100

0.84

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.70

Sift

Uncertain

0.012

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.35

MutPred

0.65

Loss of MoRF binding (P = 9e-04);

MVP

0.99

MPC

0.59

ClinPred

0.97

GERP RS

3.8

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.52

gMVP

0.95

Mutation Taster

=29/71

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over