21-44286050-G-A

Variant names:

• chr21-44286050-G-A
• rs179363876
• NM_000383.4:c.44G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000383.4(AIRE):​c.44G>A​(p.Arg15His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.22
• 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000383.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-44286049-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1481156.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 21-44286050-G-A is Pathogenic according to our data. Variant chr21-44286050-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 992986.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.44G>A	p.Arg15His	missense	Exon 1 of 14	NP_000374.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	ENST00000291582.6	TSL:1 MANE Select	c.44G>A	p.Arg15His	missense	Exon 1 of 14	ENSP00000291582.5
	AIRE	ENST00000527919.5	TSL:2	n.205G>A		non_coding_transcript_exon	Exon 1 of 14
	AIRE	ENST00000530812.5	TSL:2	n.213G>A		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000738 AC: 1 AN: 135494 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000199

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1387840 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 684740

African (AFR) AF: 0.00 AC: 0 AN: 31494

American (AMR) AF: 0.00 AC: 0 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 35666

South Asian (SAS) AF: 0.00 AC: 0 AN: 79144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5390

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077810

Other (OTH) AF: 0.00 AC: 0 AN: 57792

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Polyglandular autoimmune syndrome, type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.88		Loss of MoRF binding (P = 0.0128)
MVP		1.0
MPC		0.62
ClinPred		0.94	D
GERP RS		3.8
PromoterAI		-0.024	Neutral
Varity_R		0.92
gMVP		0.84
Mutation Taster		=25/75	disease causing (ClinVar)

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: rs179363876; hg19: chr21-45705933;