chr21-44294404-G-A

Position:

• chr21-44294404-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_000383.4(AIRE):​c.1404G>A​(p.Thr468=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,569,294 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (13 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.66

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 21-44294404-G-A is Benign according to our data. Variant chr21-44294404-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44294404-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00566 (857/151398) while in subpopulation AFR AF= 0.0165 (679/41190). AF 95% confidence interval is 0.0155. There are 11 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.1404G>A	p.Thr468=	synonymous_variant	12/14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.1404G>A	p.Thr468=	synonymous_variant	12/14	1	NM_000383.4	ENSP00000291582	P1

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 857 AN: 151280 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00545

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000944

Gnomad OTH AF: 0.00289

GnomAD3 exomes AF: 0.00208 AC: 380 AN: 182778 Hom.: 6 AF XY: 0.00169 AC XY: 171 AN XY: 101034

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00381

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.000118

Gnomad NFE exome AF: 0.000847

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00138 AC: 1957 AN: 1417896 Hom.: 13 Cov.: 31 AF XY: 0.00133 AC XY: 937 AN XY: 703108

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000682

Gnomad4 OTH exome AF: 0.00274

GnomAD4 genome AF: 0.00566 AC: 857 AN: 151398 Hom.: 11 Cov.: 31 AF XY: 0.00547 AC XY: 405 AN XY: 74000

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00545

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000944

Gnomad4 OTH AF: 0.00286

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00682

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	AIRE: BS1, BS2 -
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

Aug 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	16
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.59		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7281600; hg19: chr21-45714287;