rs34397615

chr21-44289759-C-Tchr21-44289759-C-G

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.755C>T(p.Pro252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,612,776 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. P252P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0097 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (12 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.04

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=0.0071104467).
• BP6: Variant 21-44289759-C-T is Benign according to our data. Variant chr21-44289759-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 35668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44289759-C-T is described in Lovd as [Likely_benign]. Variant chr21-44289759-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00965 (1470/152322) while in subpopulation AFR AF= 0.0334 (1390/41580). AF 95% confidence interval is 0.032. There are 28 homozygotes in gnomad4. There are 676 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.755C>T	p.Pro252Leu	missense_variant	6/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.755C>T	p.Pro252Leu	missense_variant	6/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.1488C>T		non_coding_transcript_exon_variant	6/14	2
AIRE	ENST00000530812.5	n.2505C>T		non_coding_transcript_exon_variant	4/12	2

Frequencies

GnomAD3 genomes AF: 0.00966 AC: 1471 AN: 152204 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00259 AC: 642 AN: 248000 Hom.: 9 AF XY: 0.00188 AC XY: 254 AN XY: 135078

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000224

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00103 AC: 1497 AN: 1460454 Hom.: 12 Cov.: 34 AF XY: 0.000849 AC XY: 617 AN XY: 726514

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00965 AC: 1470 AN: 152322 Hom.: 28 Cov.: 33 AF XY: 0.00908 AC XY: 676 AN XY: 74484

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.0105

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00299 AC: 362

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Benign:5

Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 25, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	0.53
Dann	Benign	0.61
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.27
Sift	Benign	0.80	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.65
MVP		0.79
MPC		0.12
ClinPred		0.00062	T
GERP RS		-0.90
Varity_R		0.031
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34397615; hg19: chr21-45709642; COSMIC: COSV99047778; COSMIC: COSV99047778;