rs2075876

Variant names:

• chr21-44289270-G-A
• rs2075876
• NM_000383.4:c.653-387G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000383.4(AIRE):​c.653-387G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 240,530 control chromosomes in the GnomAD database, including 4,716 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3578 hom., cov: 33)
  • Exomes 𝑓: 0.13 (1138 hom.)
• Consequence: AIRE NM_000383.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• Publications: 60 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.653-387G>A		intron_variant	Intron 5 of 13	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.653-387G>A		intron_variant	Intron 5 of 13	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.1239G>A		non_coding_transcript_exon_variant	Exon 5 of 14	2
AIRE	ENST00000530812.5	n.2016G>A		non_coding_transcript_exon_variant	Exon 4 of 12	2

Frequencies

GnomAD3 genomes AF: 0.193 AC: 28596 AN: 148126 Hom.: 3557 Cov.: 33

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.127 AC: 11714 AN: 92288 Hom.: 1138 Cov.: 0 AF XY: 0.127 AC XY: 6005 AN XY: 47234

African (AFR) AF: 0.306 AC: 939 AN: 3066

American (AMR) AF: 0.142 AC: 677 AN: 4778

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 328 AN: 2868

East Asian (EAS) AF: 0.341 AC: 2145 AN: 6294

South Asian (SAS) AF: 0.185 AC: 987 AN: 5348

European-Finnish (FIN) AF: 0.101 AC: 570 AN: 5658

Middle Eastern (MID) AF: 0.163 AC: 76 AN: 466

European-Non Finnish (NFE) AF: 0.0898 AC: 5233 AN: 58284

Other (OTH) AF: 0.137 AC: 759 AN: 5526

GnomAD4 genome AF: 0.193 AC: 28662 AN: 148242 Hom.: 3578 Cov.: 33 AF XY: 0.196 AC XY: 14248 AN XY: 72580

African (AFR) AF: 0.362 AC: 13617 AN: 37652

American (AMR) AF: 0.157 AC: 2405 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 529 AN: 3468

East Asian (EAS) AF: 0.383 AC: 1975 AN: 5162

South Asian (SAS) AF: 0.229 AC: 1101 AN: 4806

European-Finnish (FIN) AF: 0.116 AC: 1230 AN: 10604

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.108 AC: 7351 AN: 67990

Other (OTH) AF: 0.186 AC: 387 AN: 2086

Alfa AF: 0.132 Hom.: 6158

Bravo AF: 0.198

Asia WGS AF: 0.277 AC: 965 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.7
DANN	Benign	0.69
PhyloP100		-0.0090
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2075876; hg19: chr21-45709153;