rs61737072

Positions:

• chr21-44293100-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.1203T>C​(p.Pro401Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00856 in 1,609,130 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (587 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (453 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.51

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 21-44293100-T-C is Benign according to our data. Variant chr21-44293100-T-C is described in ClinVar as [Benign]. Clinvar id is 35657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.1203T>C	p.Pro401Pro	synonymous_variant	10/14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.1203T>C	p.Pro401Pro	synonymous_variant	10/14	1	NM_000383.4	ENSP00000291582.5

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7030 AN: 152094 Hom.: 587 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0118 AC: 2829 AN: 240148 Hom.: 207 AF XY: 0.00852 AC XY: 1113 AN XY: 130678

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000100

Gnomad FIN exome AF: 0.0000490

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00432

GnomAD4 exome AF: 0.00462 AC: 6734 AN: 1456918 Hom.: 453 Cov.: 34 AF XY: 0.00388 AC XY: 2808 AN XY: 724510

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.00942

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.000194

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.0463 AC: 7042 AN: 152212 Hom.: 587 Cov.: 32 AF XY: 0.0452 AC XY: 3363 AN XY: 74444

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0332

Alfa AF: 0.0219 Hom.: 117

Bravo AF: 0.0530

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Benign:3

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	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2012	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 05, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.96
DANN	Benign	0.44

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: rs61737072; hg19: chr21-45712983;