Variant chr21-44293094-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000383.4(AIRE):c.1197T>C(p.Ala399Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,609,302 control chromosomes in the GnomAD database, including 109,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12115 hom., cov: 33)

Exomes 𝑓: 0.36 ( 96930 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.0500

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 21-44293094-T-C is Benign according to our data. Variant chr21-44293094-T-C is described in ClinVar as [Benign]. Clinvar id is 128336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44293094-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4 link	c.1197T>C	p.Ala399Ala	synonymous_variant	Exon 10 of 14	ENST00000291582.6	NP_000374.1	O43918-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6 link	c.1197T>C	p.Ala399Ala	synonymous_variant	Exon 10 of 14	1	NM_000383.4	ENSP00000291582.5		O43918-1

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59434

AN:

151888

Hom.:

12099

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.368

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.365

GnomAD3 exomes

AF:

0.350

AC:

84601

AN:

241844

Hom.:

15214

AF XY:

0.349

AC XY:

45944

AN XY:

131530

show subpopulations

Gnomad AFR exome

AF:

0.493

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.239

Gnomad SAS exome

AF:

0.306

Gnomad FIN exome

AF:

0.417

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.358

GnomAD4 exome

AF:

0.363

AC:

529004

AN:

1457294

Hom.:

96930

Cov.:

AF XY:

0.361

AC XY:

261661

AN XY:

724716

show subpopulations

Gnomad4 AFR exome

AF:

0.497

Gnomad4 AMR exome

AF:

0.297

Gnomad4 ASJ exome

AF:

0.370

Gnomad4 EAS exome

AF:

0.282

Gnomad4 SAS exome

AF:

0.306

Gnomad4 FIN exome

AF:

0.416

Gnomad4 NFE exome

AF:

0.366

Gnomad4 OTH exome

AF:

0.371

GnomAD4 genome

AF:

0.391

AC:

59484

AN:

152008

Hom.:

12115

Cov.:

AF XY:

0.392

AC XY:

29095

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.488

Gnomad4 AMR

AF:

0.352

Gnomad4 ASJ

AF:

0.368

Gnomad4 EAS

AF:

0.257

Gnomad4 SAS

AF:

0.297

Gnomad4 FIN

AF:

0.418

Gnomad4 NFE

AF:

0.357

Gnomad4 OTH

AF:

0.363

Alfa

AF:

0.369

Hom.:

3786

Bravo

AF:

0.388

Asia WGS

AF:

0.267

AC:

931

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polyglandular autoimmune syndrome, type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

not provided

Benign:2Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

2.6

DANN

Benign

0.43

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

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