rs371136111

chr21-44294390-C-Tchr21-44294390-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000383.4(AIRE):c.1401-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,552,754 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (19 hom.)
• Consequence: AIRE NM_000383.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000009076
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.461

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 21-44294390-C-T is Benign according to our data. Variant chr21-44294390-C-T is described in ClinVar as [Benign]. Clinvar id is 446816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.1401-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.1401-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000383.4	P1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 631 AN: 151660 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.000388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.00239 AC: 397 AN: 165822 Hom.: 3 AF XY: 0.00242 AC XY: 221 AN XY: 91384

Gnomad AFR exome AF: 0.000108

Gnomad AMR exome AF: 0.000830

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0321

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00190 AC: 2656 AN: 1400976 Hom.: 19 Cov.: 31 AF XY: 0.00182 AC XY: 1266 AN XY: 694156

Gnomad4 AFR exome AF: 0.000215

Gnomad4 AMR exome AF: 0.000696

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.00137

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00416 AC: 631 AN: 151778 Hom.: 10 Cov.: 31 AF XY: 0.00577 AC XY: 428 AN XY: 74154

Gnomad4 AFR AF: 0.000387

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0445

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.00248 Hom.: 1

Bravo AF: 0.000933

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2020	Variant summary: AIRE c.1401-11C>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. 4/4 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 0.0032 in 197100 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately equal to 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 benign. To our knowledge, no occurrence of c.1401-11C>T in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Polyglandular autoimmune syndrome, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	3.6
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000091
dbscSNV1_RF	Benign	0.0
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: rs371136111; hg19: chr21-45714273;