NM_000383.4:c.1065C>T

Variant names:

• chr21-44292371-C-T
• rs201551372
• NM_000383.4:c.1065C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_000383.4(AIRE):​c.1065C>T​(p.Pro355Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,562,830 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: AIRE NM_000383.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.412
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-44292371-C-T is Benign according to our data. Variant chr21-44292371-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 528312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.412 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1065C>T	p.Pro355Pro	synonymous	Exon 9 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.1065C>T	p.Pro355Pro	synonymous	Exon 9 of 14	ENSP00000291582.5	O43918-1
	AIRE	ENST00000337909.5	TSL:1	n.526C>T		non_coding_transcript_exon	Exon 2 of 7
	AIRE	ENST00000966178.1		c.1062C>T	p.Pro354Pro	synonymous	Exon 9 of 14	ENSP00000636237.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152038 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00127 AC: 207 AN: 163372 AF XY: 0.00128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000808

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00235

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.000444

GnomAD4 exome AF: 0.00133 AC: 1878 AN: 1410674 Hom.: 3 Cov.: 32 AF XY: 0.00136 AC XY: 945 AN XY: 696812

African (AFR) AF: 0.000185 AC: 6 AN: 32490

American (AMR) AF: 0.000696 AC: 26 AN: 37366

Ashkenazi Jewish (ASJ) AF: 0.000119 AC: 3 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 37354

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80136

European-Finnish (FIN) AF: 0.00188 AC: 91 AN: 48488

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5534

European-Non Finnish (NFE) AF: 0.00157 AC: 1701 AN: 1085598

Other (OTH) AF: 0.000839 AC: 49 AN: 58424

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152156 Hom.: 1 Cov.: 33 AF XY: 0.00167 AC XY: 124 AN XY: 74396

African (AFR) AF: 0.0000482 AC: 2 AN: 41512

American (AMR) AF: 0.00353 AC: 54 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00278 AC: 189 AN: 67964

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.76
CADD	Benign	5.6
DANN	Benign	0.74
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201551372; hg19: chr21-45712254; COSMIC: COSV52397565;