rs2293657

Positions:

• chr12-66211226-A-T

Variant summary

Our verdict is Benign. Variant got -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

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 (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/exons	MANE	UniProt
IRAK3	NM_007199.3	c.437-220A>T		intron_variant		ENST00000261233.9
IRAK3	NM_001142523.2	c.254-220A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK3	ENST00000261233.9	c.437-220A>T		intron_variant		1	NM_007199.3	P1
IRAK3	ENST00000457197.2	c.254-220A>T		intron_variant		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

Gnomad4 AFR AF: 0.0802

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.290

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.260

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2293657; hg19: chr12-66605006;