rs74162061

chr21-44288401-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000383.4(AIRE):c.595G>A(p.Val199Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,612,754 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (5 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.111

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008170009).
• BP6: Variant 21-44288401-G-A is Benign according to our data. Variant chr21-44288401-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128334.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00377 (574/152326) while in subpopulation AFR AF= 0.0119 (494/41572). AF 95% confidence interval is 0.011. There are 2 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIRE	NM_000383.4	c.595G>A	p.Val199Ile	missense_variant	5/14	ENST00000291582.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIRE	ENST00000291582.6	c.595G>A	p.Val199Ile	missense_variant	5/14	1	NM_000383.4	P1
AIRE	ENST00000527919.5	n.1139G>A		non_coding_transcript_exon_variant	4/14	2
AIRE	ENST00000530812.5	n.1147G>A		non_coding_transcript_exon_variant	4/12	2

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00120 AC: 300 AN: 250342 Hom.: 0 AF XY: 0.000973 AC XY: 132 AN XY: 135650

Gnomad AFR exome AF: 0.00984

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000615 AC: 898 AN: 1460428 Hom.: 5 Cov.: 31 AF XY: 0.000575 AC XY: 418 AN XY: 726544

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00379 AC XY: 282 AN XY: 74478

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00438

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2022	Variant summary: AIRE c.595G>A (p.Val199Ile) results in a conservative amino acid change located in the SAND domain (IPR000770) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 281720 control chromosomes (gnomAD), predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of 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 a benign polymorphism found primarily in populations of African or African-American origin. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance and three as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 02, 2021	- -

Polyglandular autoimmune syndrome, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

AIRE: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	14
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.084
Sift	Benign	0.083	T
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.097
MVP		0.50
MPC		0.16
ClinPred		0.0076	T
GERP RS		0.36
Varity_R		0.061
gMVP		0.092

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: rs74162061; hg19: chr21-45708284; COSMIC: COSV99047779; COSMIC: COSV99047779;