21-44289270-G-A

Position:

• chr21-44289270-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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/exons	MANE	UniProt
AIRE	NM_000383.4	c.653-387G>A		intron_variant		ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.653-387G>A		intron_variant		1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.1239G>A		non_coding_transcript_exon_variant	5/14	2
AIRE	ENST00000530812.5	n.2016G>A		non_coding_transcript_exon_variant	4/12	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

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.341

Gnomad4 SAS exome AF: 0.185

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.0898

Gnomad4 OTH exome AF: 0.137

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

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.186

Alfa AF: 0.130 Hom.: 2478

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075876; hg19: chr21-45709153;