rs72650676

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-44293112-G-A
• chr21-44293112-G-T

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
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, ClinGen, Orphanet, Myriad Women’s Health, Ambry Genetics
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 VariationId is 458613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1215G>A	p.Pro405Pro	synonymous	Exon 10 of 14	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.1215G>A	p.Pro405Pro	synonymous	Exon 10 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.676G>A		non_coding_transcript_exon	Exon 3 of 7
	AIRE	ENST00000966178.1		c.1212G>A	p.Pro404Pro	synonymous	Exon 10 of 14	ENSP00000636237.1

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

African (AFR) AF: 0.000240 AC: 8 AN: 33366

American (AMR) AF: 0.000207 AC: 9 AN: 43426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 84968

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51108

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5620

European-Non Finnish (NFE) AF: 0.00114 AC: 1259 AN: 1108132

Other (OTH) 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

African (AFR) AF: 0.000144 AC: 6 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000497 Hom.: 0

Bravo AF: 0.000997

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.86
CADD	Benign	4.1
DANN	Uncertain	0.99
PhyloP100		-2.7
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

Other links and lift over

dbSNP: rs72650676; hg19: chr21-45712995;