rs1003854

Positions:

• chr21-44290224-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000383.4(AIRE):​c.879+156T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 983,106 control chromosomes in the GnomAD database, including 33,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4227 hom., cov: 34)
  • Exomes 𝑓: 0.26 (28937 hom.)
• Consequence: AIRE NM_000383.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-44290224-T-C is Benign according to our data. Variant chr21-44290224-T-C is described in ClinVar as [Benign]. Clinvar id is 1262941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.879+156T>C		intron_variant		ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.879+156T>C		intron_variant		1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.1612+156T>C		intron_variant, non_coding_transcript_variant		2
AIRE	ENST00000530812.5	n.2629+156T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34449 AN: 152076 Hom.: 4223 Cov.: 34

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.263 AC: 218662 AN: 830912 Hom.: 28937 Cov.: 23 AF XY: 0.264 AC XY: 101219 AN XY: 383814

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.270

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.226 AC: 34446 AN: 152194 Hom.: 4227 Cov.: 34 AF XY: 0.228 AC XY: 17000 AN XY: 74406

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.219

Alfa AF: 0.247 Hom.: 2745

Bravo AF: 0.219

Asia WGS AF: 0.192 AC: 668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.53

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

LitVar

Other links and lift over

dbSNP: rs1003854; hg19: chr21-45710107;