21-44286069-C-T

Variant names:

• chr21-44286069-C-T
• rs371796437
• NM_000383.4:c.63C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000383.4(AIRE):​c.63C>T​(p.Ala21Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,543,302 control chromosomes in the GnomAD database, including 6 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. A21A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -7.30
• 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, 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 21-44286069-C-T is Benign according to our data. Variant chr21-44286069-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 495855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00194 (2705/1391044) while in subpopulation MID AF = 0.00836 (46/5504). AF 95% confidence interval is 0.00644. There are 6 homozygotes in GnomAdExome4. There are 1325 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.63C>T	p.Ala21Ala	synonymous	Exon 1 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.63C>T	p.Ala21Ala	synonymous	Exon 1 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.63C>T	p.Ala21Ala	synonymous	Exon 1 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.224C>T		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00195 AC: 270 AN: 138408 AF XY: 0.00193

Gnomad AFR exome AF: 0.000286

Gnomad AMR exome AF: 0.000941

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.00240

GnomAD4 exome AF: 0.00194 AC: 2705 AN: 1391044 Hom.: 6 Cov.: 30 AF XY: 0.00193 AC XY: 1325 AN XY: 686380

African (AFR) AF: 0.000127 AC: 4 AN: 31544

American (AMR) AF: 0.000757 AC: 27 AN: 35662

Ashkenazi Jewish (ASJ) AF: 0.00613 AC: 154 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35690

South Asian (SAS) AF: 0.00135 AC: 107 AN: 79162

European-Finnish (FIN) AF: 0.00373 AC: 158 AN: 42334

Middle Eastern (MID) AF: 0.00836 AC: 46 AN: 5504

European-Non Finnish (NFE) AF: 0.00194 AC: 2096 AN: 1078174

Other (OTH) AF: 0.00195 AC: 113 AN: 57856

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74446

African (AFR) AF: 0.000313 AC: 13 AN: 41554

American (AMR) AF: 0.000457 AC: 7 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 67988

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.00142

Asia WGS AF: 0.00116 AC: 4 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.75
DANN	Benign	0.96
PhyloP100		-7.3
PromoterAI		0.021	Neutral
Mutation Taster		=99/1	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: rs371796437; hg19: chr21-45705952;