rs72650680

Variant names:

• chr21-44296453-C-T
• rs72650680
• NM_000383.4:c.1566+8C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000383.4(AIRE):​c.1566+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,610,772 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (11 hom.)
• Consequence: AIRE NM_000383.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001622
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -3.00
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-44296453-C-T is Benign according to our data. Variant chr21-44296453-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446817.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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.1566+8C>T		splice_region 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.1566+8C>T		splice_region intron	N/A	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.1027+8C>T		splice_region intron	N/A
	AIRE	ENST00000966178.1		c.1563+8C>T		splice_region intron	N/A	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152052 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00221 AC: 551 AN: 249830 AF XY: 0.00240

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00254 AC: 3704 AN: 1458602 Hom.: 11 Cov.: 32 AF XY: 0.00259 AC XY: 1880 AN XY: 725762

African (AFR) AF: 0.000478 AC: 16 AN: 33442

American (AMR) AF: 0.00188 AC: 84 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00261 AC: 225 AN: 86222

European-Finnish (FIN) AF: 0.000883 AC: 46 AN: 52090

Middle Eastern (MID) AF: 0.00505 AC: 29 AN: 5746

European-Non Finnish (NFE) AF: 0.00285 AC: 3168 AN: 1110310

Other (OTH) AF: 0.00209 AC: 126 AN: 60292

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152170 Hom.: 1 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74404

African (AFR) AF: 0.000578 AC: 24 AN: 41494

American (AMR) AF: 0.00229 AC: 35 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4814

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 67956

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.00211

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	not specified (2)
-	-	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	0.039
DANN	Benign	0.65
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.014
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

Other links and lift over

dbSNP: rs72650680; hg19: chr21-45716336;