21-44288394-C-T

Variant names:

• chr21-44288394-C-T
• rs878081
• NM_000383.4:c.588C>T

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.588C>T​(p.Ser196Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,612,002 control chromosomes in the GnomAD database, including 47,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3340 hom., cov: 33)
  • Exomes 𝑓: 0.24 (44510 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -5.97
• Publications: 31 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 21-44288394-C-T is Benign according to our data. Variant chr21-44288394-C-T is described in ClinVar as Benign. ClinVar VariationId is 128338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.251 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	NM_000383.4	MANE Select	c.588C>T	p.Ser196Ser	synonymous	Exon 5 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.588C>T	p.Ser196Ser	synonymous	Exon 5 of 14	ENSP00000291582.5
	AIRE	ENST00000527919.5	TSL:2	n.1132C>T		non_coding_transcript_exon	Exon 4 of 14
	AIRE	ENST00000530812.5	TSL:2	n.1140C>T		non_coding_transcript_exon	Exon 4 of 12

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28381 AN: 152124 Hom.: 3338 Cov.: 33

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.212 AC: 53021 AN: 250342 AF XY: 0.216

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.243 AC: 354032 AN: 1459758 Hom.: 44510 Cov.: 33 AF XY: 0.241 AC XY: 175378 AN XY: 726210

African (AFR) AF: 0.0396 AC: 1325 AN: 33466

American (AMR) AF: 0.190 AC: 8516 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6545 AN: 26128

East Asian (EAS) AF: 0.149 AC: 5932 AN: 39688

South Asian (SAS) AF: 0.176 AC: 15204 AN: 86236

European-Finnish (FIN) AF: 0.261 AC: 13682 AN: 52350

Middle Eastern (MID) AF: 0.245 AC: 1408 AN: 5758

European-Non Finnish (NFE) AF: 0.259 AC: 287648 AN: 1111074

Other (OTH) AF: 0.228 AC: 13772 AN: 60348

GnomAD4 genome AF: 0.186 AC: 28379 AN: 152244 Hom.: 3340 Cov.: 33 AF XY: 0.187 AC XY: 13943 AN XY: 74426

African (AFR) AF: 0.0481 AC: 1998 AN: 41574

American (AMR) AF: 0.220 AC: 3364 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3470

East Asian (EAS) AF: 0.117 AC: 608 AN: 5188

South Asian (SAS) AF: 0.174 AC: 839 AN: 4820

European-Finnish (FIN) AF: 0.262 AC: 2773 AN: 10604

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17281 AN: 67982

Other (OTH) AF: 0.176 AC: 373 AN: 2114

Alfa AF: 0.234 Hom.: 6303

Bravo AF: 0.173

Asia WGS AF: 0.129 AC: 450 AN: 3478

EpiCase AF: 0.253

EpiControl AF: 0.256

ClinVar

ClinVar submissions as Germline

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	-0.95
CADD	Benign	0.19
DANN	Benign	0.54
PhyloP100		-6.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs878081; hg19: chr21-45708277; COSMIC: COSV52393827; COSMIC: COSV52393827;