12-66203921-C-T

Variant names:

• chr12-66203921-C-T
• rs1882200
• NM_007199.3:c.316+28C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007199.3(IRAK3):​c.316+28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,573,750 control chromosomes in the GnomAD database, including 58,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4755 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53723 hom.)
• Consequence: IRAK3 NM_007199.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.273
• Publications: 17 publications found

Genes affected

IRAK3 (HGNC:17020): (interleukin 1 receptor associated kinase 3) This gene encodes a member of the interleukin-1 receptor-associated kinase protein family. Members of this family are essential components of the Toll/IL-R immune signal transduction pathways. This protein is primarily expressed in monocytes and macrophages and functions as a negative regulator of Toll-like receptor signaling. Mutations in this gene are associated with a susceptibility to asthma. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

IRAK3 Gene-Disease associations (from GenCC):

• asthma-related traits, susceptibility to, 5

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.316+28C>T		intron_variant	Intron 2 of 11	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.134-5535C>T		intron_variant	Intron 1 of 10		NP_001135995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9	c.316+28C>T		intron_variant	Intron 2 of 11	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000457197.2	c.134-5535C>T		intron_variant	Intron 1 of 10	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36749 AN: 151990 Hom.: 4749 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.242 AC: 60704 AN: 250596 AF XY: 0.247

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.270 AC: 384296 AN: 1421642 Hom.: 53723 Cov.: 25 AF XY: 0.270 AC XY: 191648 AN XY: 709792

African (AFR) AF: 0.169 AC: 5525 AN: 32614

American (AMR) AF: 0.210 AC: 9372 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7362 AN: 25834

East Asian (EAS) AF: 0.135 AC: 5325 AN: 39526

South Asian (SAS) AF: 0.213 AC: 18202 AN: 85344

European-Finnish (FIN) AF: 0.236 AC: 12616 AN: 53366

Middle Eastern (MID) AF: 0.323 AC: 1831 AN: 5670

European-Non Finnish (NFE) AF: 0.287 AC: 308476 AN: 1075660

Other (OTH) AF: 0.264 AC: 15587 AN: 59016

GnomAD4 genome AF: 0.242 AC: 36773 AN: 152108 Hom.: 4755 Cov.: 32 AF XY: 0.239 AC XY: 17798 AN XY: 74358

African (AFR) AF: 0.167 AC: 6921 AN: 41498

American (AMR) AF: 0.254 AC: 3884 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1001 AN: 3468

East Asian (EAS) AF: 0.129 AC: 666 AN: 5178

South Asian (SAS) AF: 0.215 AC: 1038 AN: 4832

European-Finnish (FIN) AF: 0.229 AC: 2422 AN: 10564

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19732 AN: 67990

Other (OTH) AF: 0.273 AC: 576 AN: 2112

Alfa AF: 0.264 Hom.: 8779

Bravo AF: 0.239

Asia WGS AF: 0.173 AC: 603 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		0.27
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: rs1882200; hg19: chr12-66597701; COSMIC: COSV54160242;