21-44289685-C-T

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.681C>T(p.Gly227=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,612,616 control chromosomes in the GnomAD database, including 57,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G227G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (4060 hom., cov: 33)
  • Exomes 𝑓: 0.26 (53911 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -2.24

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=-0.57).
• BP6: Variant 21-44289685-C-T is Benign according to our data. Variant chr21-44289685-C-T is described in ClinVar as [Benign]. Clinvar id is 128339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44289685-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.681C>T	p.Gly227=	synonymous_variant	6/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.681C>T	p.Gly227=	synonymous_variant	6/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.1414C>T		non_coding_transcript_exon_variant	6/14	2
AIRE	ENST00000530812.5	n.2431C>T		non_coding_transcript_exon_variant	4/12	2

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30502 AN: 152040 Hom.: 4057 Cov.: 33

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.226 AC: 56380 AN: 249922 Hom.: 7482 AF XY: 0.228 AC XY: 30977 AN XY: 135640

Gnomad AFR exome AF: 0.0479

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.00501

Gnomad SAS exome AF: 0.172

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.282

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.263 AC: 384500 AN: 1460458 Hom.: 53911 Cov.: 43 AF XY: 0.261 AC XY: 189649 AN XY: 726518

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.241

Gnomad4 ASJ exome AF: 0.187

Gnomad4 EAS exome AF: 0.00524

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome AF: 0.201 AC: 30510 AN: 152158 Hom.: 4060 Cov.: 33 AF XY: 0.199 AC XY: 14821 AN XY: 74392

Gnomad4 AFR AF: 0.0540

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.199

Alfa AF: 0.244 Hom.: 6305

Bravo AF: 0.185

Asia WGS AF: 0.0720 AC: 248 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	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 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

Polyglandular autoimmune syndrome, type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.90
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1055311; hg19: chr21-45709568; COSMIC: COSV52393886; COSMIC: COSV52393886;