rs1800521

Positions:

• chr21-44293094-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000383.4(AIRE):​c.1197T>C​(p.Ala399=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.0500

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]

ACMG classification

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/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.1197T>C	p.Ala399=	synonymous_variant	10/14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.1197T>C	p.Ala399=	synonymous_variant	10/14	1	NM_000383.4	ENSP00000291582	P1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59434 AN: 151888 Hom.: 12099 Cov.: 33

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

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.: 46 AF XY: 0.361 AC XY: 261661 AN XY: 724716

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.: 33 AF XY: 0.392 AC XY: 29095 AN XY: 74310

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:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Polyglandular autoimmune syndrome, type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2 Other: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	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Other links and lift over

dbSNP: rs1800521; hg19: chr21-45712977; COSMIC: COSV52392298;