21-44287550-C-T

Position:

• chr21-44287550-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.497C>T	p.Pro166Leu	missense_variant	4/14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.497C>T	p.Pro166Leu	missense_variant	4/14	1	NM_000383.4	ENSP00000291582	P1
AIRE	ENST00000527919.5	n.1041C>T		non_coding_transcript_exon_variant	3/14	2
AIRE	ENST00000530812.5	n.1049C>T		non_coding_transcript_exon_variant	3/12	2

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

GnomAD3 exomes AF: 0.00117 AC: 195 AN: 166682 Hom.: 2 AF XY: 0.000836 AC XY: 74 AN XY: 88542

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 SAS exome AF: 0.0000855

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

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000397

Gnomad4 OTH exome AF: 0.00135

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

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00205 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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11910214; hg19: chr21-45707433; COSMIC: COSV52395041; COSMIC: COSV52395041;