21-44287550-C-T

Variant names:

• chr21-44287550-C-T
• rs11910214
• NM_000383.4:c.497C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000383.4(AIRE):​c.497C>T​(p.Pro166Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,559,260 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P166P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (9 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0940
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006411791).
• BP6: Variant 21-44287550-C-T is Benign according to our data. Variant chr21-44287550-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00521 (794/152272) while in subpopulation AFR AF = 0.018 (750/41554). AF 95% confidence interval is 0.017. There are 8 homozygotes in GnomAd4. There are 395 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

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.497C>T	p.Pro166Leu	missense	Exon 4 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.497C>T	p.Pro166Leu	missense	Exon 4 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.497C>T	p.Pro166Leu	missense	Exon 4 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.1041C>T		non_coding_transcript_exon	Exon 3 of 14

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 791 AN: 152154 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.000147

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00117 AC: 195 AN: 166682 AF XY: 0.000836

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000542

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 0.000585 AC: 823 AN: 1406988 Hom.: 9 Cov.: 32 AF XY: 0.000482 AC XY: 335 AN XY: 694682

African (AFR) AF: 0.0208 AC: 669 AN: 32216

American (AMR) AF: 0.000626 AC: 23 AN: 36770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 36906

South Asian (SAS) AF: 0.000100 AC: 8 AN: 79784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48482

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5608

European-Non Finnish (NFE) AF: 0.0000397 AC: 43 AN: 1083678

Other (OTH) AF: 0.00135 AC: 79 AN: 58308

GnomAD4 genome AF: 0.00521 AC: 794 AN: 152272 Hom.: 8 Cov.: 32 AF XY: 0.00531 AC XY: 395 AN XY: 74446

African (AFR) AF: 0.0180 AC: 750 AN: 41554

American (AMR) AF: 0.00131 AC: 20 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68008

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00197 Hom.: 2

Bravo AF: 0.00603

ESP6500AA AF: 0.0159 AC: 68

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000889 AC: 101

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Polyglandular autoimmune syndrome, type 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.4
DANN	Benign	0.39
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.91	L
PhyloP100		-0.094
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.18
Sift	Benign	0.089	T
Sift4G	Benign	0.29	T
Polyphen		0.0080	B
Vest4		0.11
MVP		0.95
MPC		0.12
ClinPred		0.0055	T
GERP RS		1.4
Varity_R		0.050
gMVP		0.20
Mutation Taster		=97/3	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: rs11910214; hg19: chr21-45707433; COSMIC: COSV52395041; COSMIC: COSV52395041;