chr21-44294411-C-A

Position:

• chr21-44294411-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000383.4(AIRE):​c.1411C>A​(p.Arg471Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,704 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R471C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIRE	NM_000383.4	c.1411C>A	p.Arg471Ser	missense_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.1411C>A	p.Arg471Ser	missense_variant	12/14	1	NM_000383.4	ENSP00000291582.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000530 AC: 1 AN: 188644 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 104298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000645

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000854 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.49	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.017	D
Sift4G	Benign	0.077	T
Polyphen		0.65	P
Vest4		0.43
MutPred		0.52		Loss of methylation at R471 (P = 0.0491);
MVP		0.96
MPC		0.14
ClinPred		0.19	T
GERP RS		2.7
Varity_R		0.21
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74203920; hg19: chr21-45714294;