rs779510704

chr21-44294454-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000383.4(AIRE):c.1454A>T(p.Glu485Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,566,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.07

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23318645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.1454A>T	p.Glu485Val	missense_variant	12/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.1454A>T	p.Glu485Val	missense_variant	12/14	1	NM_000383.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151304 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000496 AC: 9 AN: 181360 Hom.: 0 AF XY: 0.0000697 AC XY: 7 AN XY: 100432

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000876

Gnomad OTH exome AF: 0.000213

GnomAD4 exome AF: 0.0000445 AC: 63 AN: 1415292 Hom.: 0 Cov.: 31 AF XY: 0.0000456 AC XY: 32 AN XY: 701766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000538

Gnomad4 OTH exome AF: 0.0000509

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151422 Hom.: 0 Cov.: 31 AF XY: 0.0000405 AC XY: 3 AN XY: 74002

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000173 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	This sequence change replaces glutamic acid with valine at codon 485 of the AIRE protein (p.Glu485Val). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs779510704, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.70	D;N;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Benign	0.057	T
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.47
MutPred		0.26		Loss of solvent accessibility (P = 0.0721);
MVP		0.82
MPC		0.19
ClinPred		0.052	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs779510704; hg19: chr21-45714337;