rs7281600

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-44294404-G-A
• chr21-44294404-G-C
• chr21-44294404-G-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_000383.4(AIRE):​c.1404G>A​(p.Thr468Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,569,294 control chromosomes in the GnomAD database, including 24 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. T468T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (13 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 21-44294404-G-A is Benign according to our data. Variant chr21-44294404-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00566 (857/151398) while in subpopulation AFR AF = 0.0165 (679/41190). AF 95% confidence interval is 0.0155. There are 11 homozygotes in GnomAd4. There are 405 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

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>A	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>A	p.Thr468Thr	synonymous	Exon 12 of 14	ENSP00000291582.5
	AIRE	ENST00000337909.5	TSL:1	n.865G>A		non_coding_transcript_exon	Exon 5 of 7
	AIRE	ENST00000966178.1		c.1401G>A	p.Thr467Thr	synonymous	Exon 12 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 857 AN: 151280 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00545

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000944

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00208 AC: 380 AN: 182778 AF XY: 0.00169

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00381

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000118

Gnomad NFE exome AF: 0.000847

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00138 AC: 1957 AN: 1417896 Hom.: 13 Cov.: 31 AF XY: 0.00133 AC XY: 937 AN XY: 703108

African (AFR) AF: 0.0185 AC: 610 AN: 32988

American (AMR) AF: 0.00253 AC: 103 AN: 40746

Ashkenazi Jewish (ASJ) AF: 0.00362 AC: 92 AN: 25430

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

South Asian (SAS) AF: 0.00238 AC: 194 AN: 81588

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

Middle Eastern (MID) AF: 0.00860 AC: 47 AN: 5462

European-Non Finnish (NFE) AF: 0.000682 AC: 749 AN: 1097516

Other (OTH) AF: 0.00274 AC: 162 AN: 59070

GnomAD4 genome AF: 0.00566 AC: 857 AN: 151398 Hom.: 11 Cov.: 31 AF XY: 0.00547 AC XY: 405 AN XY: 74000

African (AFR) AF: 0.0165 AC: 679 AN: 41190

American (AMR) AF: 0.00545 AC: 83 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4784

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

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000944 AC: 64 AN: 67800

Other (OTH) AF: 0.00286 AC: 6 AN: 2098

Alfa AF: 0.00207 Hom.: 1

Bravo AF: 0.00682

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	16
DANN	Benign	0.64
PhyloP100		-1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.59		Position offset: 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;