rs1800521

Variant names:

• chr21-44293094-T-C
• rs1800521
• NM_000383.4:c.1197T>C

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.1197T>C​(p.Ala399Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,609,302 control chromosomes in the GnomAD database, including 109,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12115 hom., cov: 33)
  • Exomes 𝑓: 0.36 (96930 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 0.0500
• 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=-0.96).
• BP6: Variant 21-44293094-T-C is Benign according to our data. Variant chr21-44293094-T-C is described in ClinVar as Benign. ClinVar VariationId is 128336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 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.1197T>C	p.Ala399Ala	synonymous	Exon 10 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.1197T>C	p.Ala399Ala	synonymous	Exon 10 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.658T>C		non_coding_transcript_exon	Exon 3 of 7
	AIRE	ENST00000966178.1		c.1194T>C	p.Ala398Ala	synonymous	Exon 10 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59434 AN: 151888 Hom.: 12099 Cov.: 33

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.365

GnomAD2 exomes AF: 0.350 AC: 84601 AN: 241844 AF XY: 0.349

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.295

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.239

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.363 AC: 529004 AN: 1457294 Hom.: 96930 Cov.: 46 AF XY: 0.361 AC XY: 261661 AN XY: 724716

African (AFR) AF: 0.497 AC: 16600 AN: 33430

American (AMR) AF: 0.297 AC: 13143 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 9607 AN: 25962

East Asian (EAS) AF: 0.282 AC: 11163 AN: 39572

South Asian (SAS) AF: 0.306 AC: 26284 AN: 85898

European-Finnish (FIN) AF: 0.416 AC: 21482 AN: 51680

Middle Eastern (MID) AF: 0.387 AC: 2195 AN: 5672

European-Non Finnish (NFE) AF: 0.366 AC: 406230 AN: 1110618

Other (OTH) AF: 0.371 AC: 22300 AN: 60140

GnomAD4 genome AF: 0.391 AC: 59484 AN: 152008 Hom.: 12115 Cov.: 33 AF XY: 0.392 AC XY: 29095 AN XY: 74310

African (AFR) AF: 0.488 AC: 20238 AN: 41448

American (AMR) AF: 0.352 AC: 5373 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1278 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1326 AN: 5160

South Asian (SAS) AF: 0.297 AC: 1435 AN: 4826

European-Finnish (FIN) AF: 0.418 AC: 4433 AN: 10594

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24227 AN: 67918

Other (OTH) AF: 0.363 AC: 763 AN: 2102

Alfa AF: 0.366 Hom.: 5433

Bravo AF: 0.388

Asia WGS AF: 0.267 AC: 931 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.96
CADD	Benign	2.6
DANN	Benign	0.43
PhyloP100		0.050
Mutation Taster		=88/12	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: rs1800521; hg19: chr21-45712977; COSMIC: COSV52392298;