21-44286017-A-T

Position:

• chr21-44286017-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000383.4(AIRE):​c.11A>T​(p.Asp4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain HSR (size 104) in uniprot entity AIRE_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_000383.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.11A>T	p.Asp4Val	missense_variant	1/14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.11A>T	p.Asp4Val	missense_variant	1/14	1	NM_000383.4	ENSP00000291582	P1
AIRE	ENST00000527919.5	n.172A>T		non_coding_transcript_exon_variant	1/14	2
AIRE	ENST00000530812.5	n.180A>T		non_coding_transcript_exon_variant	1/12	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2021

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIRE protein function. This variant has not been reported in the literature in individuals with AIRE-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces aspartic acid with valine at codon 4 of the AIRE protein (p.Asp4Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.68		Gain of helix (P = 0.0225);
MVP		0.99
MPC		0.67
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.34
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45705900;