rs113512196

Variant names:

• chr21-44292984-G-C
• rs113512196
• NM_000383.4:c.1096-9G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-44292984-G-C
• chr21-44292984-G-T

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.1096-9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,611,902 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (55 hom.)
• Consequence: AIRE NM_000383.4 intron
• Scores: Splicing: ADA: 0.00003243
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.402
• 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, 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=-0.87).
• BP6: Variant 21-44292984-G-C is Benign according to our data. Variant chr21-44292984-G-C is described in ClinVar as Benign. ClinVar VariationId is 128330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0544 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.1096-9G>C		intron	N/A	NP_000374.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIRE	ENST00000291582.6	TSL:1 MANE Select	c.1096-9G>C		intron	N/A	ENSP00000291582.5
	AIRE	ENST00000337909.5	TSL:1	n.557-9G>C		intron	N/A
	AIRE	ENST00000397994.8	TSL:5	n.557-9G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2226 AN: 152136 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00381 AC: 943 AN: 247554 AF XY: 0.00294

Gnomad AFR exome AF: 0.0540

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000807

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00162 AC: 2362 AN: 1459648 Hom.: 55 Cov.: 31 AF XY: 0.00141 AC XY: 1022 AN XY: 726144

African (AFR) AF: 0.0565 AC: 1890 AN: 33446

American (AMR) AF: 0.00271 AC: 121 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52090

Middle Eastern (MID) AF: 0.00617 AC: 34 AN: 5510

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111604

Other (OTH) AF: 0.00388 AC: 234 AN: 60294

GnomAD4 genome AF: 0.0146 AC: 2227 AN: 152254 Hom.: 45 Cov.: 33 AF XY: 0.0142 AC XY: 1056 AN XY: 74440

African (AFR) AF: 0.0506 AC: 2103 AN: 41534

American (AMR) AF: 0.00581 AC: 89 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67998

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00438 Hom.: 10

Bravo AF: 0.0168

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.87
CADD	Benign	15
DANN	Benign	0.59
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113512196; hg19: chr21-45712867;