rs386833675

Variant names:

• chr21-44291179-TGCCTGTCCCCTCC-T
• rs386833675
• NM_000383.4:c.967_979delCTGTCCCCTCCGC

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_000383.4(AIRE):​c.967_979delCTGTCCCCTCCGC​(p.Leu323SerfsTer51) variant causes a frameshift change. The variant allele was found at a frequency of 0.00103 in 1,606,780 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000696656: A mice model of this 13-bp deletion displaying a mild autoimmune phenotype characterized by a disturbance of medullary epithelial compartment, increased levels of activated T cells and autoantibodies against multiple organs has been reported (Hubert_2009)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L323L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: AIRE NM_000383.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 O:1
• Conservation: PhyloP100: 7.08
• Publications: 36 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: Pathogenic. The variant received 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000696656: A mice model of this 13-bp deletion displaying a mild autoimmune phenotype characterized by a disturbance of medullary epithelial compartment, increased levels of activated T cells and autoantibodies against multiple organs has been reported (Hubert_2009).; SCV004048245: An experimental study has shown that this sequence change has a dominant negative effect on the gene regulation of tested AIRE-regulated genes (Oftedal, Bergithe E., et al).; SCV000329056: Published functional studies indicate the variant may have a minor dominant negative effect, which in heterozygotes could lead to atypical phenotypes with later onset and reduced penetrance (Oftedal et al., 2015); PMID: 28911151, 27588307, 28769929, 27219120, 26912174, 25707324, 26084028, 27253668, 28323927
• PP5: Variant 21-44291179-TGCCTGTCCCCTCC-T is Pathogenic according to our data. Variant chr21-44291179-TGCCTGTCCCCTCC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.967_979delCTGTCCCCTCCGC	p.Leu323SerfsTer51	frameshift	Exon 8 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.967_979delCTGTCCCCTCCGC	p.Leu323SerfsTer51	frameshift	Exon 8 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.428_440delCTGTCCCCTCCGC		non_coding_transcript_exon	Exon 1 of 7
	AIRE	ENST00000966178.1		c.964_976delCTGTCCCCTCCGC	p.Leu322SerfsTer51	frameshift	Exon 8 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000506 AC: 123 AN: 242922 AF XY: 0.000491

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000172

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.000997

GnomAD4 exome AF: 0.00108 AC: 1570 AN: 1454530 Hom.: 3 AF XY: 0.00104 AC XY: 753 AN XY: 723754

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.0000671 AC: 3 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86214

European-Finnish (FIN) AF: 0.000213 AC: 10 AN: 47000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5380

European-Non Finnish (NFE) AF: 0.00132 AC: 1463 AN: 1111746

Other (OTH) AF: 0.00139 AC: 84 AN: 60250

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74450

African (AFR) AF: 0.000193 AC: 8 AN: 41538

American (AMR) AF: 0.000261 AC: 4 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67990

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000650

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	Polyglandular autoimmune syndrome, type 1 (20)
8	-	-	not provided (8)
1	-	-	AIRE-related disorder (1)
1	-	-	Autoimmune polyglandular syndrome type 1, with reversible metaphyseal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386833675; hg19: chr21-45711062;