21-44286069-C-T

Position:

• chr21-44286069-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000383.4(AIRE):​c.63C>T​(p.Ala21Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,543,302 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -7.30

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 21-44286069-C-T is Benign according to our data. Variant chr21-44286069-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 495855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44286069-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-7.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00194 (2705/1391044) while in subpopulation MID AF= 0.00836 (46/5504). AF 95% confidence interval is 0.00644. There are 6 homozygotes in gnomad4_exome. There are 1325 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.63C>T	p.Ala21Ala	synonymous_variant	1/14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.63C>T	p.Ala21Ala	synonymous_variant	1/14	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.224C>T		non_coding_transcript_exon_variant	1/14	2
AIRE	ENST00000530812.5	n.232C>T		non_coding_transcript_exon_variant	1/12	2

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00195 AC: 270 AN: 138408 Hom.: 1 AF XY: 0.00193 AC XY: 145 AN XY: 75310

Gnomad AFR exome AF: 0.000286

Gnomad AMR exome AF: 0.000941

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.00240

GnomAD4 exome AF: 0.00194 AC: 2705 AN: 1391044 Hom.: 6 Cov.: 30 AF XY: 0.00193 AC XY: 1325 AN XY: 686380

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.000757

Gnomad4 ASJ exome AF: 0.00613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00373

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74446

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.00142

Asia WGS AF: 0.00116 AC: 4 AN: 3464

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2016	- -
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, 2022	AIRE: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 21, 2018

- -

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	-0.40
CADD	Benign	0.75
DANN	Benign	0.96

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: rs371796437; hg19: chr21-45705952;