rs179363881

Variant names:

• chr21-44286662-G-A
• NM_000383.4:c.238G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-44286662-G-A
• chr21-44286662-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000383.4(AIRE):​c.238G>A​(p.Val80Met) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V80L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.77

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_pathogenic. Variant got 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.238G>A	p.Val80Met	missense_variant	Exon 2 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.238G>A	p.Val80Met	missense_variant	Exon 2 of 14	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.399G>A		non_coding_transcript_exon_variant	Exon 2 of 14	2
AIRE	ENST00000530812.5	n.407G>A		non_coding_transcript_exon_variant	Exon 2 of 12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AIRE c.238G>A (p.Val80Met) results in a conservative amino acid change located in the HSR domain (IPR004865) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250996 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.238G>A in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 3016461). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Polyglandular autoimmune syndrome, type 1 Uncertain:1

Feb 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIRE protein function. This variant has not been reported in the literature in individuals affected with AIRE-related conditions. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 80 of the AIRE protein (p.Val80Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.57
Sift	Benign	0.057	T
Sift4G	Benign	0.063	T
Polyphen		0.99	D
Vest4		0.59
MutPred		0.88		Loss of ubiquitination at K83 (P = 0.1498);
MVP		0.97
MPC		0.55
ClinPred		0.81	D
GERP RS		2.8
Varity_R		0.21
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr21-45706545;