rs1800520

chr21-44290023-C-Gchr21-44290023-C-Tchr21-44290023-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000383.4(AIRE):c.834C>G(p.Ser278Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,610,112 control chromosomes in the GnomAD database, including 14,899 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S278S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2711 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12188 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.168

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 -16 ACMG points.

• BP6: Variant 21-44290023-C-G is Benign according to our data. Variant chr21-44290023-C-G is described in ClinVar as [Benign]. Clinvar id is 128340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44290023-C-G is described in Lovd as [Likely_benign]. Variant chr21-44290023-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.834C>G	p.Ser278Arg	missense_variant	7/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.834C>G	p.Ser278Arg	missense_variant	7/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.1567C>G		non_coding_transcript_exon_variant	7/14	2
AIRE	ENST00000530812.5	n.2584C>G		non_coding_transcript_exon_variant	5/12	2

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24937 AN: 152018 Hom.: 2704 Cov.: 33

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0938

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.142 AC: 34231 AN: 240646 Hom.: 3317 AF XY: 0.140 AC XY: 18469 AN XY: 131566

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.378

Gnomad SAS exome AF: 0.184

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0935

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.115 AC: 168045 AN: 1457976 Hom.: 12188 Cov.: 34 AF XY: 0.116 AC XY: 84324 AN XY: 725244

Gnomad4 AFR exome AF: 0.299

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.358

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0956

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.164 AC: 24974 AN: 152136 Hom.: 2711 Cov.: 33 AF XY: 0.166 AC XY: 12382 AN XY: 74388

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0937

Gnomad4 OTH AF: 0.165

Alfa AF: 0.0857 Hom.: 226

Bravo AF: 0.171

TwinsUK AF: 0.0984 AC: 365

ALSPAC AF: 0.104 AC: 402

ESP6500AA AF: 0.284 AC: 1240

ESP6500EA AF: 0.0916 AC: 787

ExAC AF: 0.142 AC: 17082

Asia WGS AF: 0.241 AC: 835 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

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.	Sep 16, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21505073, 19322061, 25525159, 12542742) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 11, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	1.4
Dann	Benign	0.59
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00021	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.20
Sift	Benign	0.69	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.11		Loss of glycosylation at S278 (P = 0.0099);
MPC		0.13
ClinPred		0.00029	T
GERP RS		1.6
Varity_R		0.029
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: -35

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800520; hg19: chr21-45709906; COSMIC: COSV52394292; COSMIC: COSV52394292;