21-44290023-C-G

Variant names:

• chr21-44290023-C-G
• rs1800520
• NM_000383.4:c.834C>G

Variant summary

Our verdict is Benign. The variant received -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. 14/23 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:12
• Conservation: PhyloP100: -0.168
• Publications: 47 publications found

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 Gene-Disease associations (from GenCC):

• autoimmune polyendocrine syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Myriad Women’s Health, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.834C>G	p.Ser278Arg	missense_variant	Exon 7 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.834C>G	p.Ser278Arg	missense_variant	Exon 7 of 14	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.1567C>G		non_coding_transcript_exon_variant	Exon 7 of 14	2
AIRE	ENST00000530812.5	n.2584C>G		non_coding_transcript_exon_variant	Exon 5 of 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

GnomAD2 exomes AF: 0.142 AC: 34231 AN: 240646 AF XY: 0.140

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 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

African (AFR) AF: 0.299 AC: 9990 AN: 33456

American (AMR) AF: 0.104 AC: 4605 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3106 AN: 26034

East Asian (EAS) AF: 0.358 AC: 14178 AN: 39564

South Asian (SAS) AF: 0.181 AC: 15543 AN: 85964

European-Finnish (FIN) AF: 0.110 AC: 5683 AN: 51642

Middle Eastern (MID) AF: 0.126 AC: 729 AN: 5768

European-Non Finnish (NFE) AF: 0.0956 AC: 106230 AN: 1111046

Other (OTH) AF: 0.133 AC: 7981 AN: 60140

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

African (AFR) AF: 0.286 AC: 11865 AN: 41488

American (AMR) AF: 0.127 AC: 1944 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 442 AN: 3472

East Asian (EAS) AF: 0.365 AC: 1876 AN: 5146

South Asian (SAS) AF: 0.191 AC: 923 AN: 4822

European-Finnish (FIN) AF: 0.108 AC: 1147 AN: 10608

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0937 AC: 6372 AN: 67978

Other (OTH) AF: 0.165 AC: 348 AN: 2112

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21505073, 19322061, 25525159, 12542742) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 11, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polyglandular autoimmune syndrome, type 1 Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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
PhyloP100		-0.17
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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