rs72650680

Positions:

chr21-44296453-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000383.4(AIRE):c.1566+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,610,772 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 11 hom. )

Consequence

AIRE
NM_000383.4 splice_region, intron

Scores

Splicing: ADA: 0.00001622

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -3.00

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 21-44296453-C-T is Benign according to our data. Variant chr21-44296453-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446817.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr21-44296453-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4 linkuse as main transcript	c.1566+8C>T		splice_region_variant, intron_variant		ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6 linkuse as main transcript	c.1566+8C>T		splice_region_variant, intron_variant		1	NM_000383.4	ENSP00000291582	P1	O43918-1

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00340

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00221

AC:

551

AN:

249830

Hom.:

AF XY:

0.00240

AC XY:

326

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.000807

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00268

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00322

Gnomad OTH exome

AF:

0.00263

GnomAD4 exome

AF:

0.00254

AC:

3704

AN:

1458602

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1880

AN XY:

725762

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00261

Gnomad4 FIN exome

AF:

0.000883

Gnomad4 NFE exome

AF:

0.00285

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00208

AC:

317

AN:

152170

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00338

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.00211

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	AIRE: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2018	Variant summary: AIRE c.1566+8C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0022 in 276242 control chromosomes (3 homozygotes), predominantly within the Non-Finnish European subpopulation in the gnomAD database at a frequency of 0.0032, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), suggesting the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1566+8C>T in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign, benign, or uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2016	- -

Polyglandular autoimmune syndrome, type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.039

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.014

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over