21-44293832-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000383.4(AIRE):c.1322C>T(p.Thr441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,596,942 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T441A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4O:1

Conservation

PhyloP100: -0.620

Publications

12 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.116511256).

BP6

Variant 21-44293832-C-T is Benign according to our data. Variant chr21-44293832-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35660.

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

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.1322C>T	p.Thr441Met	missense	Exon 11 of 14	NP_000374.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1322C>T	p.Thr441Met	missense	Exon 11 of 14	ENSP00000291582.5
AIRE	ENST00000337909.5	TSL:1	n.783C>T		non_coding_transcript_exon	Exon 4 of 7
AIRE	ENST00000966178.1		c.1319C>T	p.Thr440Met	missense	Exon 11 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00147

AC:

351

AN:

238236

AF XY:

0.00159

show subpopulations

Gnomad AFR exome

AF:

0.000315

Gnomad AMR exome

AF:

0.000610

Gnomad ASJ exome

AF:

0.00362

Gnomad EAS exome

AF:

0.0000549

Gnomad FIN exome

AF:

0.000167

Gnomad NFE exome

AF:

0.00173

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.00165

AC:

2389

AN:

1444798

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

1193

AN XY:

719206

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33430

American (AMR)

AF:

0.000671

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00262

AC:

226

AN:

86202

European-Finnish (FIN)

AF:

0.000158

AC:

AN:

38046

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

4866

European-Non Finnish (NFE)

AF:

0.00169

AC:

1879

AN:

1111628

Other (OTH)

AF:

0.00221

AC:

133

AN:

60162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

152

305

457

610

762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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

AF:

0.00103

AC:

156

AN:

152144

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

41482

American (AMR)

AF:

0.000327

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

67960

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.000975

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00130

AC:

157

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Polyglandular autoimmune syndrome, type 1 (7)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.2

PhyloP100

-0.62

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.57

Sift

Benign

0.078

Sift4G

Benign

0.085

Polyphen

0.97

Vest4

0.73

MVP

0.97

MPC

0.25

ClinPred

0.013

GERP RS

0.63

Varity_R

0.038

gMVP

0.31

Mutation Taster

=95/5

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over