21-44293112-G-A

Variant names:

• chr21-44293112-G-A
• rs72650676
• NM_000383.4:c.1215G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Very_Strong BP7 BS2_Supporting

The NM_000383.4(AIRE):​c.1215G>A​(p.Pro405Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,603,960 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P405P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00092 (2 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.75

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.198).
• BP6: Variant 21-44293112-G-A is Benign according to our data. Variant chr21-44293112-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44293112-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.1215G>A	p.Pro405Pro	synonymous_variant	Exon 10 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.1215G>A	p.Pro405Pro	synonymous_variant	Exon 10 of 14	1	NM_000383.4	ENSP00000291582.5

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152174 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000469 AC: 107 AN: 228376 AF XY: 0.000524

Gnomad AFR exome AF: 0.000143

Gnomad AMR exome AF: 0.000215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000916 AC: 1330 AN: 1451668 Hom.: 2 Cov.: 34 AF XY: 0.000893 AC XY: 644 AN XY: 721370

Gnomad4 AFR exome AF: 0.000240 AC: 8 AN: 33366

Gnomad4 AMR exome AF: 0.000207 AC: 9 AN: 43426

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25774

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39304

Gnomad4 SAS exome AF: 0.0000235 AC: 2 AN: 84968

Gnomad4 FIN exome AF: 0.0000196 AC: 1 AN: 51108

Gnomad4 NFE exome AF: 0.00114 AC: 1259 AN: 1108132

Gnomad4 Remaining exome AF: 0.000834 AC: 50 AN: 59970

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152292 Hom.: 1 Cov.: 31 AF XY: 0.000752 AC XY: 56 AN XY: 74468

Gnomad4 AFR AF: 0.000144 AC: 0.000144349 AN: 0.000144349

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000897 AC: 0.000897191 AN: 0.000897191

Gnomad4 OTH AF: 0.000473 AC: 0.000473037 AN: 0.000473037

Alfa AF: 0.000497 Hom.: 0

Bravo AF: 0.000997

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 02, 2021

GeneDx

Significance: Likely 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	-0.86
CADD	Benign	4.1
DANN	Uncertain	0.99
Mutation Taster		=95/5	polymorphism

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: rs72650676; hg19: chr21-45712995;