dbSNP rs751032: AIRE:c.-230T>C (chr21-44285777-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000383.4(AIRE):c.-230T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 361,478 control chromosomes in the GnomAD database, including 142,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 61614 hom., cov: 33)

Exomes 𝑓: 0.88 ( 80841 hom. )

Consequence

AIRE
NM_000383.4 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.369

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 21-44285777-T-C is Benign according to our data. Variant chr21-44285777-T-C is described in ClinVar as [Benign]. Clinvar id is 1165016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.-230T>C		upstream_gene_variant		ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
AIRE	ENST00000291582.6 link	c.-230T>C	upstream_gene_variant	1	NM_000383.4	ENSP00000291582.5	O43918-1
AIRE	ENST00000527919.5 link	n.-69T>C	upstream_gene_variant	2
AIRE	ENST00000530812.5 link	n.-61T>C	upstream_gene_variant	2

Frequencies

GnomAD3 genomes

AF:

0.898

AC:

136537

AN:

152094

Hom.:

61543

Cov.:

show subpopulations

Gnomad AFR

AF:

0.977

Gnomad AMI

AF:

0.945

Gnomad AMR

AF:

0.871

Gnomad ASJ

AF:

0.849

Gnomad EAS

AF:

0.708

Gnomad SAS

AF:

0.908

Gnomad FIN

AF:

0.882

Gnomad MID

AF:

0.908

Gnomad NFE

AF:

0.874

Gnomad OTH

AF:

0.879

GnomAD4 exome

AF:

0.878

AC:

183646

AN:

209266

Hom.:

80841

AF XY:

0.878

AC XY:

98492

AN XY:

112174

show subpopulations

Gnomad4 AFR exome

AF:

0.975

Gnomad4 AMR exome

AF:

0.881

Gnomad4 ASJ exome

AF:

0.846

Gnomad4 EAS exome

AF:

0.757

Gnomad4 SAS exome

AF:

0.905

Gnomad4 FIN exome

AF:

0.878

Gnomad4 NFE exome

AF:

0.883

Gnomad4 OTH exome

AF:

0.867

GnomAD4 genome

AF:

0.898

AC:

136667

AN:

152212

Hom.:

61614

Cov.:

AF XY:

0.896

AC XY:

66634

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.977

Gnomad4 AMR

AF:

0.871

Gnomad4 ASJ

AF:

0.849

Gnomad4 EAS

AF:

0.707

Gnomad4 SAS

AF:

0.909

Gnomad4 FIN

AF:

0.882

Gnomad4 NFE

AF:

0.874

Gnomad4 OTH

AF:

0.881

Alfa

AF:

0.883

Hom.:

9137

Bravo

AF:

0.898

Asia WGS

AF:

0.837

AC:

2912

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25978041) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polyglandular autoimmune syndrome, type 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.2

DANN

Benign

0.54

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over