NM_000383.4:c.1411C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000383.4(AIRE):c.1411C>T(p.Arg471Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,574,200 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R471H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 23 hom., cov: 31)

Exomes 𝑓: 0.013 ( 152 hom. )

Consequence

AIRE
NM_000383.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0790

Publications

26 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, 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

AIRE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014049828).

BP6

Variant 21-44294411-C-T is Benign according to our data. Variant chr21-44294411-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1686/151696) while in subpopulation NFE AF = 0.0145 (982/67850). AF 95% confidence interval is 0.0137. There are 23 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 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.1411C>T	p.Arg471Cys	missense	Exon 12 of 14	NP_000374.1	O43918-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1411C>T	p.Arg471Cys	missense	Exon 12 of 14	ENSP00000291582.5	O43918-1
AIRE	ENST00000337909.5	TSL:1	n.872C>T		non_coding_transcript_exon	Exon 5 of 7
AIRE	ENST00000966178.1		c.1408C>T	p.Arg470Cys	missense	Exon 12 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1683

AN:

151580

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00544

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.0457

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0145

Gnomad OTH

AF:

0.00962

GnomAD2 exomes

AF:

0.00924

AC:

1743

AN:

188644

AF XY:

0.00924

show subpopulations

Gnomad AFR exome

AF:

0.00158

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.00549

Gnomad EAS exome

AF:

0.000129

Gnomad FIN exome

AF:

0.0377

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.00758

GnomAD4 exome

AF:

0.0129

AC:

18420

AN:

1422504

Hom.:

152

Cov.:

AF XY:

0.0125

AC XY:

8841

AN XY:

705756

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

33086

American (AMR)

AF:

0.00357

AC:

148

AN:

41480

Ashkenazi Jewish (ASJ)

AF:

0.00502

AC:

128

AN:

25488

East Asian (EAS)

AF:

0.000233

AC:

AN:

38624

South Asian (SAS)

AF:

0.000719

AC:

AN:

82088

European-Finnish (FIN)

AF:

0.0366

AC:

1362

AN:

37166

Middle Eastern (MID)

AF:

0.00181

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.0146

AC:

16102

AN:

1099840

Other (OTH)

AF:

0.00930

AC:

551

AN:

59218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

808

1616

2424

3232

4040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.0111

AC:

1686

AN:

151696

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

921

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.00242

AC:

100

AN:

41354

American (AMR)

AF:

0.00544

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.000417

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.0457

AC:

483

AN:

10572

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0145

AC:

982

AN:

67850

Other (OTH)

AF:

0.00951

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

162

243

324

405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0125

Hom.:

Bravo

AF:

0.00775

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00249

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00849

AC:

994

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (4)

Polyglandular autoimmune syndrome, type 1 (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.054

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.57

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

0.75

PhyloP100

0.079

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.56

Sift

Benign

0.033

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.36

MVP

0.98

MPC

0.16

ClinPred

0.0093

GERP RS

2.7

Varity_R

0.13

gMVP

0.45

Mutation Taster

=95/5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over