rs933150

Variant names:

• chr21-44292705-G-A
• rs933150
• NM_000383.4:c.1096-288G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000383.4(AIRE):​c.1096-288G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 152,064 control chromosomes in the GnomAD database, including 6,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.30 (6821 hom., cov: 33)
• Consequence: AIRE NM_000383.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.939
• Publications: 16 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, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-44292705-G-A is Benign according to our data. Variant chr21-44292705-G-A is described in ClinVar as Benign. ClinVar VariationId is 1184789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000383.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.1096-288G>A		intron	N/A	NP_000374.1	O43918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1096-288G>A		intron	N/A	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.557-288G>A		intron	N/A
	AIRE	ENST00000966178.1		c.1093-288G>A		intron	N/A	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45109 AN: 151946 Hom.: 6815 Cov.: 33

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.272

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.297 AC: 45131 AN: 152064 Hom.: 6821 Cov.: 33 AF XY: 0.298 AC XY: 22117 AN XY: 74342

African (AFR) AF: 0.307 AC: 12748 AN: 41492

American (AMR) AF: 0.331 AC: 5071 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 924 AN: 3470

East Asian (EAS) AF: 0.230 AC: 1189 AN: 5168

South Asian (SAS) AF: 0.167 AC: 804 AN: 4816

European-Finnish (FIN) AF: 0.323 AC: 3420 AN: 10580

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20066 AN: 67924

Other (OTH) AF: 0.271 AC: 572 AN: 2112

Alfa AF: 0.296 Hom.: 18243

Bravo AF: 0.297

Asia WGS AF: 0.181 AC: 630 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Polyglandular autoimmune syndrome, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.46
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs933150; hg19: chr21-45712588;