21-44294404-G-C

Variant names:

• chr21-44294404-G-C
• rs7281600
• NM_000383.4:c.1404G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4 BP6_Moderate BP7

The NM_000383.4(AIRE):​c.1404G>C​(p.Thr468Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000395 in 1,569,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T468T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.66
• 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.205).
• BP6: Variant 21-44294404-G-C is Benign according to our data. Variant chr21-44294404-G-C is described in ClinVar as Benign. ClinVar VariationId is 458615.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.66 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.1404G>C	p.Thr468Thr	synonymous	Exon 12 of 14	NP_000374.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1404G>C	p.Thr468Thr	synonymous	Exon 12 of 14	ENSP00000291582.5
	AIRE	ENST00000337909.5	TSL:1	n.865G>C		non_coding_transcript_exon	Exon 5 of 7
	AIRE	ENST00000966178.1		c.1401G>C	p.Thr467Thr	synonymous	Exon 12 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151286 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000257 AC: 47 AN: 182778 AF XY: 0.000129

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000409 AC: 58 AN: 1417922 Hom.: 0 Cov.: 31 AF XY: 0.0000242 AC XY: 17 AN XY: 703114

African (AFR) AF: 0.0000606 AC: 2 AN: 33002

American (AMR) AF: 0.00130 AC: 53 AN: 40748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25432

East Asian (EAS) AF: 0.00 AC: 0 AN: 38368

South Asian (SAS) AF: 0.00 AC: 0 AN: 81588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1097524

Other (OTH) AF: 0.0000169 AC: 1 AN: 59070

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151286 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73874

African (AFR) AF: 0.00 AC: 0 AN: 41072

American (AMR) AF: 0.000263 AC: 4 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67808

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.000132

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.23
DANN	Benign	0.64
PhyloP100		-1.7

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: rs7281600; hg19: chr21-45714287;