21-44286007-A-T

Variant names:

• chr21-44286007-A-T
• rs121434258
• NM_000383.4:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_000383.4(AIRE):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000458 in 1,529,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: AIRE NM_000383.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -1.01
• Publications: 8 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 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 92 pathogenic variants. Next in-frame start position is after 184 codons. Genomic position: 44288356. Lost 0.336 part of the original CDS.
• PS1: Another start lost variant in NM_000383.4 (AIRE) was described as [Pathogenic] in ClinVar
• PP5: Variant 21-44286007-A-T is Pathogenic according to our data. Variant chr21-44286007-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.162A>T		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151882 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000363 AC: 5 AN: 1378002 Hom.: 0 Cov.: 30 AF XY: 0.00000441 AC XY: 3 AN XY: 679800

African (AFR) AF: 0.00 AC: 0 AN: 31086

American (AMR) AF: 0.00 AC: 0 AN: 35454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24914

East Asian (EAS) AF: 0.00 AC: 0 AN: 35340

South Asian (SAS) AF: 0.00 AC: 0 AN: 78900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4538

European-Non Finnish (NFE) AF: 0.00000465 AC: 5 AN: 1075544

Other (OTH) AF: 0.00 AC: 0 AN: 57408

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151882 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74192

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Polyglandular autoimmune syndrome, type 1 (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	0.98
DANN	Benign	0.60
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.46	T
PhyloP100		-1.0
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.50
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.75
MutPred		0.86		Loss of catalytic residue at M1 (P = 0.0532)
MVP		0.77
ClinPred		0.062	T
GERP RS		-1.9
PromoterAI		-0.043	Neutral
Varity_R		0.11
gMVP		0.62
Mutation Taster		=7/193	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: rs121434258; hg19: chr21-45705890;