rs192215705

Positions:

• chr21-44297651-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.1567-5C>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 0.00286 in 1,610,980 control chromosomes in the GnomAD database, including 20 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (19 hom.)
• Consequence: AIRE NM_000383.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006648
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.482

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 21-44297651-C-T is Benign according to our data. Variant chr21-44297651-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 35662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44297651-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00183 (278/152296) while in subpopulation SAS AF= 0.00933 (45/4824). AF 95% confidence interval is 0.00716. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.1567-5C>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	c.1567-5C>T		splice_region_variant, intron_variant		1	NM_000383.4	ENSP00000291582.5

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152178 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00288 AC: 714 AN: 248286 Hom.: 6 AF XY: 0.00333 AC XY: 450 AN XY: 134998

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00251

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00954

Gnomad FIN exome AF: 0.000335

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00296 AC: 4322 AN: 1458684 Hom.: 19 Cov.: 30 AF XY: 0.00312 AC XY: 2264 AN XY: 725762

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00925

Gnomad4 FIN exome AF: 0.000311

Gnomad4 NFE exome AF: 0.00285

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152296 Hom.: 1 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74478

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00933

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00258 Hom.: 1

Bravo AF: 0.00185

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	AIRE: BP4, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2018	Variant summary: AIRE c.1567-5C>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. 4/5 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 0.0027 in 274874 control chromosomes, predominantly at a frequency of 0.0095 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.1567-5C>T in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "benign." Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2016	- -

Polyglandular autoimmune syndrome, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

AIRE-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.84
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0020
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: rs192215705; hg19: chr21-45717534;