rs3746964

Variant names:

• chr21-44286105-T-C
• rs3746964
• NM_000383.4:c.99T>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.99T>C​(p.Ala33Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0554 in 1,546,618 control chromosomes in the GnomAD database, including 13,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (5926 hom., cov: 32)
  • Exomes 𝑓: 0.042 (7454 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.36
• Publications: 10 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=-0.71).
• BP6: Variant 21-44286105-T-C is Benign according to our data. Variant chr21-44286105-T-C is described in ClinVar as Benign. ClinVar VariationId is 35669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 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.99T>C	p.Ala33Ala	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.99T>C	p.Ala33Ala	synonymous	Exon 1 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000966178.1		c.99T>C	p.Ala33Ala	synonymous	Exon 1 of 14	ENSP00000636237.1
	AIRE	ENST00000527919.5	TSL:2	n.260T>C		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26395 AN: 151962 Hom.: 5891 Cov.: 32

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.0800

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.0910 AC: 12890 AN: 141686 AF XY: 0.0847

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.0796

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0425 AC: 59241 AN: 1394548 Hom.: 7454 Cov.: 30 AF XY: 0.0425 AC XY: 29262 AN XY: 688016

African (AFR) AF: 0.547 AC: 17207 AN: 31480

American (AMR) AF: 0.0904 AC: 3223 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 1928 AN: 25128

East Asian (EAS) AF: 0.302 AC: 10757 AN: 35656

South Asian (SAS) AF: 0.0762 AC: 6035 AN: 79188

European-Finnish (FIN) AF: 0.0117 AC: 533 AN: 45470

Middle Eastern (MID) AF: 0.105 AC: 583 AN: 5572

European-Non Finnish (NFE) AF: 0.0135 AC: 14551 AN: 1078508

Other (OTH) AF: 0.0764 AC: 4424 AN: 57892

GnomAD4 genome AF: 0.174 AC: 26482 AN: 152070 Hom.: 5926 Cov.: 32 AF XY: 0.172 AC XY: 12768 AN XY: 74346

African (AFR) AF: 0.512 AC: 21204 AN: 41426

American (AMR) AF: 0.0968 AC: 1480 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3470

East Asian (EAS) AF: 0.305 AC: 1569 AN: 5146

South Asian (SAS) AF: 0.0799 AC: 386 AN: 4832

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10614

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0161 AC: 1095 AN: 67972

Other (OTH) AF: 0.153 AC: 322 AN: 2110

Alfa AF: 0.0696 Hom.: 644

Bravo AF: 0.200

Asia WGS AF: 0.189 AC: 657 AN: 3456

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	3	Polyglandular autoimmune syndrome, type 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.4
DANN	Benign	0.64
PhyloP100		-4.4
PromoterAI		0.024	Neutral
Mutation Taster		=99/1	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: rs3746964; hg19: chr21-45705988; COSMIC: COSV52392455; COSMIC: COSV52392455;