21-44294476-C-T

Variant names:

• chr21-44294476-C-T
• rs72650679
• NM_000383.4:c.1476C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_000383.4(AIRE):​c.1476C>T​(p.Pro492Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,542,820 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P492P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.58
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 21-44294476-C-T is Benign according to our data. Variant chr21-44294476-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.58 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1476C>T	p.Pro492Pro	synonymous	Exon 12 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.1476C>T	p.Pro492Pro	synonymous	Exon 12 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.937C>T		non_coding_transcript_exon	Exon 5 of 7
	AIRE	ENST00000966178.1		c.1473C>T	p.Pro491Pro	synonymous	Exon 12 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.000890 AC: 135 AN: 151734 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000952 AC: 144 AN: 151250 AF XY: 0.000929

Gnomad AFR exome AF: 0.000344

Gnomad AMR exome AF: 0.000199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000592

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.000486

GnomAD4 exome AF: 0.00167 AC: 2325 AN: 1390970 Hom.: 2 Cov.: 31 AF XY: 0.00165 AC XY: 1135 AN XY: 687906

African (AFR) AF: 0.000279 AC: 9 AN: 32266

American (AMR) AF: 0.000135 AC: 5 AN: 36966

Ashkenazi Jewish (ASJ) AF: 0.0000409 AC: 1 AN: 24478

East Asian (EAS) AF: 0.00 AC: 0 AN: 37178

South Asian (SAS) AF: 0.0000507 AC: 4 AN: 78880

European-Finnish (FIN) AF: 0.000593 AC: 21 AN: 35412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5404

European-Non Finnish (NFE) AF: 0.00207 AC: 2236 AN: 1082520

Other (OTH) AF: 0.000847 AC: 49 AN: 57866

GnomAD4 genome AF: 0.000889 AC: 135 AN: 151850 Hom.: 0 Cov.: 31 AF XY: 0.000916 AC XY: 68 AN XY: 74222

African (AFR) AF: 0.000435 AC: 18 AN: 41396

American (AMR) AF: 0.000458 AC: 7 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00158 AC: 107 AN: 67914

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000914

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Polyglandular autoimmune syndrome, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.15
DANN	Benign	0.73
PhyloP100		-4.6
Mutation Taster		=100/0	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: rs72650679; hg19: chr21-45714359;