rs1168773

Positions:

• chr12-66196952-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000545837.1(IRAK3):​c.206A>G​(p.Tyr69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,535,268 control chromosomes in the GnomAD database, including 2,335 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.071 (1244 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (1091 hom.)
• Consequence: IRAK3 ENST00000545837.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020825267).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK3	NM_007199.3	c.134-6759A>G		intron_variant		ENST00000261233.9
IRAK3	NM_001142523.2	c.133+7520A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK3	ENST00000545837.1	c.206A>G	p.Tyr69Cys	missense_variant	2/2	1
IRAK3	ENST00000261233.9	c.134-6759A>G		intron_variant		1	NM_007199.3	P1
IRAK3	ENST00000457197.2	c.133+7520A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0709 AC: 10782 AN: 152120 Hom.: 1243 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0584

GnomAD3 exomes AF: 0.0147 AC: 1967 AN: 133466 Hom.: 211 AF XY: 0.0115 AC XY: 838 AN XY: 72690

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000449

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00771 AC: 10669 AN: 1383030 Hom.: 1091 Cov.: 31 AF XY: 0.00684 AC XY: 4671 AN XY: 682422

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000772

Gnomad4 FIN exome AF: 0.0000590

Gnomad4 NFE exome AF: 0.000942

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0709 AC: 10797 AN: 152238 Hom.: 1244 Cov.: 32 AF XY: 0.0679 AC XY: 5055 AN XY: 74462

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.0296

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0578

Alfa AF: 0.0133 Hom.: 189

Bravo AF: 0.0822

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0115 AC: 172

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.13
ClinPred		0.088	T
GERP RS		4.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1168773; hg19: chr12-66590732;