chr21-44293846-T-G

Variant names:

• chr21-44293846-T-G
• rs1555873106
• NM_000383.4:c.1336T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000383.4(AIRE):​c.1336T>G​(p.Cys446Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. C446C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.07
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autoimmune polyendocrine syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Myriad Women’s Health, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.1336T>G	p.Cys446Gly	missense_variant	Exon 11 of 14	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.1336T>G	p.Cys446Gly	missense_variant	Exon 11 of 14	1	NM_000383.4	ENSP00000291582.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Polyglandular autoimmune syndrome, type 1 Uncertain:1

Mar 24, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	23
DANN	Benign	0.66
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.65
Sift	Benign	0.11	T
Sift4G	Uncertain	0.010	D
Polyphen		0.0	B
Vest4		0.94
MutPred		0.98		Loss of stability (P = 0.0384);
MVP		0.95
MPC		0.15
ClinPred		0.63	D
GERP RS		3.9
Varity_R		0.36
gMVP		0.79
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs1555873106; hg19: chr21-45713729;