NM_000383.4:c.-230T>C

Variant names:

• chr21-44285777-T-C
• rs751032
• NM_000383.4:c.-230T>C

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.-230T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 361,478 control chromosomes in the GnomAD database, including 142,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61614 hom., cov: 33)
  • Exomes 𝑓: 0.88 (80841 hom.)
• Consequence: AIRE NM_000383.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.369
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-44285777-T-C is Benign according to our data. Variant chr21-44285777-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.-230T>C		upstream_gene_variant		ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.-230T>C		upstream_gene_variant		1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.-69T>C		upstream_gene_variant		2
AIRE	ENST00000530812.5	n.-61T>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136537 AN: 152094 Hom.: 61543 Cov.: 33

Gnomad AFR AF: 0.977

Gnomad AMI AF: 0.945

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.874

Gnomad OTH AF: 0.879

GnomAD4 exome AF: 0.878 AC: 183646 AN: 209266 Hom.: 80841 AF XY: 0.878 AC XY: 98492 AN XY: 112174

African (AFR) AF: 0.975 AC: 3680 AN: 3774

American (AMR) AF: 0.881 AC: 3258 AN: 3696

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 4879 AN: 5768

East Asian (EAS) AF: 0.757 AC: 8633 AN: 11408

South Asian (SAS) AF: 0.905 AC: 17316 AN: 19136

European-Finnish (FIN) AF: 0.878 AC: 16874 AN: 19228

Middle Eastern (MID) AF: 0.873 AC: 826 AN: 946

European-Non Finnish (NFE) AF: 0.883 AC: 117600 AN: 133114

Other (OTH) AF: 0.867 AC: 10580 AN: 12196

GnomAD4 genome AF: 0.898 AC: 136667 AN: 152212 Hom.: 61614 Cov.: 33 AF XY: 0.896 AC XY: 66634 AN XY: 74396

African (AFR) AF: 0.977 AC: 40623 AN: 41574

American (AMR) AF: 0.871 AC: 13331 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2946 AN: 3470

East Asian (EAS) AF: 0.707 AC: 3636 AN: 5140

South Asian (SAS) AF: 0.909 AC: 4383 AN: 4824

European-Finnish (FIN) AF: 0.882 AC: 9350 AN: 10602

Middle Eastern (MID) AF: 0.918 AC: 268 AN: 292

European-Non Finnish (NFE) AF: 0.874 AC: 59406 AN: 67986

Other (OTH) AF: 0.881 AC: 1862 AN: 2114

Alfa AF: 0.883 Hom.: 9137

Bravo AF: 0.898

Asia WGS AF: 0.837 AC: 2912 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25978041) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polyglandular autoimmune syndrome, type 1 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.2
DANN	Benign	0.54
PhyloP100		-0.37
PromoterAI		-0.044	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751032; hg19: chr21-45705660;