NM_000383.4:c.1344C>G

Variant names:

• chr21-44293854-C-G
• rs201131119
• NM_000383.4:c.1344C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000383.4(AIRE):​c.1344C>G​(p.His448Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H448H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AIRE NM_000383.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.111
• Publications: 0 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, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000383.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.1344C>G	p.His448Gln	missense	Exon 11 of 14	NP_000374.1	O43918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1344C>G	p.His448Gln	missense	Exon 11 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.805C>G		non_coding_transcript_exon	Exon 4 of 7
	AIRE	ENST00000966178.1		c.1341C>G	p.His447Gln	missense	Exon 11 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Polyglandular autoimmune syndrome, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.11
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.42
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.17	B
Vest4		0.30
MutPred		0.45		Gain of sheet (P = 0.1451)
MVP		0.95
MPC		0.12
ClinPred		0.16	T
GERP RS		1.8
Varity_R		0.091
gMVP		0.20
Mutation Taster		=73/27	polymorphism

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: rs201131119; hg19: chr21-45713737;