21-44295931-A-G

Variant names:

• chr21-44295931-A-G
• rs760426
• NM_000383.4:c.1504-452A>G

Variant summary

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

The NM_000383.4(AIRE):​c.1504-452A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 151,994 control chromosomes in the GnomAD database, including 2,165 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 0.16 (2165 hom., cov: 33)
• Consequence: AIRE NM_000383.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 29 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.1504-452A>G		intron_variant	Intron 12 of 13	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.1504-452A>G		intron_variant	Intron 12 of 13	1	NM_000383.4	ENSP00000291582.5

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24071 AN: 151876 Hom.: 2160 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.159 AC: 24100 AN: 151994 Hom.: 2165 Cov.: 33 AF XY: 0.160 AC XY: 11905 AN XY: 74338

African (AFR) AF: 0.173 AC: 7182 AN: 41396

American (AMR) AF: 0.173 AC: 2652 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3468

East Asian (EAS) AF: 0.383 AC: 1977 AN: 5162

South Asian (SAS) AF: 0.142 AC: 683 AN: 4810

European-Finnish (FIN) AF: 0.112 AC: 1191 AN: 10612

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9562 AN: 67950

Other (OTH) AF: 0.149 AC: 314 AN: 2106

Alfa AF: 0.144 Hom.: 3819

Bravo AF: 0.166

Asia WGS AF: 0.233 AC: 813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.33
DANN	Benign	0.52
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760426; hg19: chr21-45715814;