21-44289685-C-T

Variant names:

• chr21-44289685-C-T
• rs1055311
• NM_000383.4:c.681C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000383.4(AIRE):​c.681C>T​(p.Gly227Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,612,616 control chromosomes in the GnomAD database, including 57,971 homozygotes. 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. G227G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (4060 hom., cov: 33)
  • Exomes 𝑓: 0.26 (53911 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -2.24
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 21-44289685-C-T is Benign according to our data. Variant chr21-44289685-C-T is described in ClinVar as Benign. ClinVar VariationId is 128339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

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.681C>T	p.Gly227Gly	synonymous	Exon 6 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.681C>T	p.Gly227Gly	synonymous	Exon 6 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.681C>T	p.Gly227Gly	synonymous	Exon 6 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.1414C>T		non_coding_transcript_exon	Exon 6 of 14

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30502 AN: 152040 Hom.: 4057 Cov.: 33

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.226 AC: 56380 AN: 249922 AF XY: 0.228

Gnomad AFR exome AF: 0.0479

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.00501

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.282

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.263 AC: 384500 AN: 1460458 Hom.: 53911 Cov.: 43 AF XY: 0.261 AC XY: 189649 AN XY: 726518

African (AFR) AF: 0.0431 AC: 1444 AN: 33480

American (AMR) AF: 0.241 AC: 10761 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4880 AN: 26120

East Asian (EAS) AF: 0.00524 AC: 208 AN: 39700

South Asian (SAS) AF: 0.175 AC: 15111 AN: 86258

European-Finnish (FIN) AF: 0.316 AC: 16447 AN: 52114

Middle Eastern (MID) AF: 0.130 AC: 750 AN: 5768

European-Non Finnish (NFE) AF: 0.289 AC: 321118 AN: 1111930

Other (OTH) AF: 0.228 AC: 13781 AN: 60374

GnomAD4 genome AF: 0.201 AC: 30510 AN: 152158 Hom.: 4060 Cov.: 33 AF XY: 0.199 AC XY: 14821 AN XY: 74392

African (AFR) AF: 0.0540 AC: 2245 AN: 41550

American (AMR) AF: 0.198 AC: 3029 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3470

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5182

South Asian (SAS) AF: 0.169 AC: 814 AN: 4822

European-Finnish (FIN) AF: 0.328 AC: 3467 AN: 10586

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19532 AN: 67942

Other (OTH) AF: 0.199 AC: 419 AN: 2108

Alfa AF: 0.240 Hom.: 7591

Bravo AF: 0.185

Asia WGS AF: 0.0720 AC: 248 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.265

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Polyglandular autoimmune syndrome, type 1 (3)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.90
DANN	Benign	0.57
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1055311; hg19: chr21-45709568; COSMIC: COSV52393886; COSMIC: COSV52393886;