chr21-44288394-C-T

Position:

chr21-44288394-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000383.4(AIRE):c.588C>T(p.Ser196=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,612,002 control chromosomes in the GnomAD database, including 47,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3340 hom., cov: 33)

Exomes 𝑓: 0.24 ( 44510 hom. )

Consequence

AIRE
NM_000383.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -5.97

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 21-44288394-C-T is Benign according to our data. Variant chr21-44288394-C-T is described in ClinVar as [Benign]. Clinvar id is 128338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44288394-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4 linkuse as main transcript	c.588C>T	p.Ser196=	synonymous_variant	5/14	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.588C>T	p.Ser196=	synonymous_variant	5/14	1	NM_000383.4	ENSP00000291582	P1	O43918-1
AIRE	ENST00000527919.5 linkuse as main transcript	n.1132C>T		non_coding_transcript_exon_variant	4/14	2
AIRE	ENST00000530812.5 linkuse as main transcript	n.1140C>T		non_coding_transcript_exon_variant	4/12	2

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28381

AN:

152124

Hom.:

3338

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0482

Gnomad AMI

AF:

0.243

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.176

GnomAD3 exomes

AF:

0.212

AC:

53021

AN:

250342

Hom.:

6176

AF XY:

0.216

AC XY:

29243

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.0458

Gnomad AMR exome

AF:

0.192

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.100

Gnomad SAS exome

AF:

0.177

Gnomad FIN exome

AF:

0.261

Gnomad NFE exome

AF:

0.256

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.243

AC:

354032

AN:

1459758

Hom.:

44510

Cov.:

AF XY:

0.241

AC XY:

175378

AN XY:

726210

show subpopulations

Gnomad4 AFR exome

AF:

0.0396

Gnomad4 AMR exome

AF:

0.190

Gnomad4 ASJ exome

AF:

0.250

Gnomad4 EAS exome

AF:

0.149

Gnomad4 SAS exome

AF:

0.176

Gnomad4 FIN exome

AF:

0.261

Gnomad4 NFE exome

AF:

0.259

Gnomad4 OTH exome

AF:

0.228

GnomAD4 genome

AF:

0.186

AC:

28379

AN:

152244

Hom.:

3340

Cov.:

AF XY:

0.187

AC XY:

13943

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0481

Gnomad4 AMR

AF:

0.220

Gnomad4 ASJ

AF:

0.247

Gnomad4 EAS

AF:

0.117

Gnomad4 SAS

AF:

0.174

Gnomad4 FIN

AF:

0.262

Gnomad4 NFE

AF:

0.254

Gnomad4 OTH

AF:

0.176

Alfa

AF:

0.235

Hom.:

5570

Bravo

AF:

0.173

Asia WGS

AF:

0.129

AC:

450

AN:

3478

EpiCase

AF:

0.253

EpiControl

AF:

0.256

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polyglandular autoimmune syndrome, type 1

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.19

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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