rs1133779

Variant names:

• chr21-44297667-T-C
• rs1133779
• NM_000383.4:c.1578T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-44297667-T-C
• chr21-44297667-T-A

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.1578T>C​(p.Asp526Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,611,030 control chromosomes in the GnomAD database, including 155,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19394 hom., cov: 33)
  • Exomes 𝑓: 0.43 (135917 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.97
• 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=-0.72).
• BP6: Variant 21-44297667-T-C is Benign according to our data. Variant chr21-44297667-T-C is described in ClinVar as Benign. ClinVar VariationId is 128337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 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.1578T>C	p.Asp526Asp	synonymous	Exon 14 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.1578T>C	p.Asp526Asp	synonymous	Exon 14 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.1039T>C		non_coding_transcript_exon	Exon 7 of 7
	AIRE	ENST00000966178.1		c.1575T>C	p.Asp525Asp	synonymous	Exon 14 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74726 AN: 151966 Hom.: 19354 Cov.: 33

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.466

GnomAD2 exomes AF: 0.459 AC: 114178 AN: 248750 AF XY: 0.450

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.446

Gnomad EAS exome AF: 0.659

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.438

GnomAD4 exome AF: 0.428 AC: 623919 AN: 1458944 Hom.: 135917 Cov.: 40 AF XY: 0.426 AC XY: 308893 AN XY: 725868

African (AFR) AF: 0.657 AC: 21986 AN: 33452

American (AMR) AF: 0.499 AC: 22314 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11595 AN: 26132

East Asian (EAS) AF: 0.653 AC: 25930 AN: 39682

South Asian (SAS) AF: 0.416 AC: 35874 AN: 86236

European-Finnish (FIN) AF: 0.406 AC: 20984 AN: 51638

Middle Eastern (MID) AF: 0.493 AC: 2838 AN: 5760

European-Non Finnish (NFE) AF: 0.410 AC: 455470 AN: 1110994

Other (OTH) AF: 0.446 AC: 26928 AN: 60344

GnomAD4 genome AF: 0.492 AC: 74819 AN: 152086 Hom.: 19394 Cov.: 33 AF XY: 0.494 AC XY: 36738 AN XY: 74366

African (AFR) AF: 0.647 AC: 26840 AN: 41492

American (AMR) AF: 0.497 AC: 7609 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1578 AN: 3470

East Asian (EAS) AF: 0.667 AC: 3444 AN: 5162

South Asian (SAS) AF: 0.428 AC: 2061 AN: 4816

European-Finnish (FIN) AF: 0.410 AC: 4345 AN: 10588

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27455 AN: 67950

Other (OTH) AF: 0.470 AC: 989 AN: 2106

Alfa AF: 0.441 Hom.: 20341

Bravo AF: 0.505

Asia WGS AF: 0.509 AC: 1775 AN: 3478

EpiCase AF: 0.418

EpiControl AF: 0.412

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 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.098
DANN	Benign	0.65
PhyloP100		-2.0
Mutation Taster		=97/3	polymorphism (auto)

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: rs1133779; hg19: chr21-45717550; COSMIC: COSV52392318; COSMIC: COSV52392318;