rs3746964

Positions:

• chr21-44286105-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000383.4(AIRE):​c.99T>C​(p.Ala33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0554 in 1,546,618 control chromosomes in the GnomAD database, including 13,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (5926 hom., cov: 32)
  • Exomes 𝑓: 0.042 (7454 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.36

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 21-44286105-T-C is Benign according to our data. Variant chr21-44286105-T-C is described in ClinVar as [Benign]. Clinvar id is 35669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44286105-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.99T>C	p.Ala33=	synonymous_variant	1/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.99T>C	p.Ala33=	synonymous_variant	1/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.260T>C		non_coding_transcript_exon_variant	1/14	2
AIRE	ENST00000530812.5	n.268T>C		non_coding_transcript_exon_variant	1/12	2

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26395 AN: 151962 Hom.: 5891 Cov.: 32

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.0800

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.0910 AC: 12890 AN: 141686 Hom.: 1730 AF XY: 0.0847 AC XY: 6508 AN XY: 76840

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.0796

Gnomad EAS exome AF: 0.305

Gnomad SAS exome AF: 0.0776

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0425 AC: 59241 AN: 1394548 Hom.: 7454 Cov.: 30 AF XY: 0.0425 AC XY: 29262 AN XY: 688016

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.0904

Gnomad4 ASJ exome AF: 0.0767

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.0762

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0764

GnomAD4 genome AF: 0.174 AC: 26482 AN: 152070 Hom.: 5926 Cov.: 32 AF XY: 0.172 AC XY: 12768 AN XY: 74346

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.0968

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.0799

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.153

Alfa AF: 0.0696 Hom.: 644

Bravo AF: 0.200

Asia WGS AF: 0.189 AC: 657 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polyglandular autoimmune syndrome, type 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2010	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 10, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.4
DANN	Benign	0.64

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: rs3746964; hg19: chr21-45705988; COSMIC: COSV52392455; COSMIC: COSV52392455;