rs2293657

Variant names:

• chr12-66211226-A-T
• rs2293657
• NM_007199.3:c.437-220A>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.437-220A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,176 control chromosomes in the GnomAD database, including 4,230 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 0.22 (4230 hom., cov: 32)
• Consequence: IRAK3 NM_007199.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.567
• Publications: 1 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 = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.437-220A>T		intron_variant	Intron 4 of 11	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.254-220A>T		intron_variant	Intron 3 of 10		NP_001135995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9	c.437-220A>T		intron_variant	Intron 4 of 11	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000457197.2	c.254-220A>T		intron_variant	Intron 3 of 10	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32994 AN: 152058 Hom.: 4227 Cov.: 32

Gnomad AFR AF: 0.0804

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.263

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.217 AC: 32996 AN: 152176 Hom.: 4230 Cov.: 32 AF XY: 0.215 AC XY: 16001 AN XY: 74396

African (AFR) AF: 0.0802 AC: 3331 AN: 41550

American (AMR) AF: 0.246 AC: 3765 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1004 AN: 3468

East Asian (EAS) AF: 0.130 AC: 672 AN: 5174

South Asian (SAS) AF: 0.213 AC: 1029 AN: 4826

European-Finnish (FIN) AF: 0.229 AC: 2428 AN: 10582

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19691 AN: 67982

Other (OTH) AF: 0.260 AC: 548 AN: 2110

Alfa AF: 0.243 Hom.: 638

Bravo AF: 0.211

Asia WGS AF: 0.164 AC: 569 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	3.4
DANN	Benign	0.75
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2293657; hg19: chr12-66605006;