rs1003854

Variant names:

• chr21-44290224-T-C
• rs1003854
• NM_000383.4:c.879+156T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-44290224-T-C
• chr21-44290224-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000383.4(AIRE):​c.879+156T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 983,106 control chromosomes in the GnomAD database, including 33,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4227 hom., cov: 34)
  • Exomes 𝑓: 0.26 (28937 hom.)
• Consequence: AIRE NM_000383.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.32
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-44290224-T-C is Benign according to our data. Variant chr21-44290224-T-C is described in ClinVar as Benign. ClinVar VariationId is 1262941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIRE	NM_000383.4	c.879+156T>C		intron_variant	Intron 7 of 13	ENST00000291582.6	NP_000374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIRE	ENST00000291582.6	c.879+156T>C		intron_variant	Intron 7 of 13	1	NM_000383.4	ENSP00000291582.5
AIRE	ENST00000527919.5	n.1612+156T>C		intron_variant	Intron 7 of 13	2
AIRE	ENST00000530812.5	n.2629+156T>C		intron_variant	Intron 5 of 11	2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34449 AN: 152076 Hom.: 4223 Cov.: 34

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.263 AC: 218662 AN: 830912 Hom.: 28937 Cov.: 23 AF XY: 0.264 AC XY: 101219 AN XY: 383814

African (AFR) AF: 0.121 AC: 1901 AN: 15738

American (AMR) AF: 0.233 AC: 228 AN: 980

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 1372 AN: 5146

East Asian (EAS) AF: 0.270 AC: 978 AN: 3620

South Asian (SAS) AF: 0.187 AC: 3070 AN: 16414

European-Finnish (FIN) AF: 0.261 AC: 72 AN: 276

Middle Eastern (MID) AF: 0.278 AC: 448 AN: 1610

European-Non Finnish (NFE) AF: 0.268 AC: 203501 AN: 759896

Other (OTH) AF: 0.260 AC: 7092 AN: 27232

GnomAD4 genome AF: 0.226 AC: 34446 AN: 152194 Hom.: 4227 Cov.: 34 AF XY: 0.228 AC XY: 17000 AN XY: 74406

African (AFR) AF: 0.131 AC: 5432 AN: 41538

American (AMR) AF: 0.268 AC: 4107 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 924 AN: 3472

East Asian (EAS) AF: 0.266 AC: 1373 AN: 5164

South Asian (SAS) AF: 0.186 AC: 898 AN: 4828

European-Finnish (FIN) AF: 0.282 AC: 2994 AN: 10600

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17919 AN: 67974

Other (OTH) AF: 0.219 AC: 463 AN: 2110

Alfa AF: 0.247 Hom.: 4444

Bravo AF: 0.219

Asia WGS AF: 0.192 AC: 668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.53
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs1003854; hg19: chr21-45710107;