rs1821777

Variant names:

• chr12-66212448-C-T
• rs1821777
• NM_007199.3:c.588+851C>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.588+851C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 152,026 control chromosomes in the GnomAD database, including 4,753 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 (4753 hom., cov: 31)
• Consequence: IRAK3 NM_007199.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.925
• Publications: 14 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=-0.9).
• 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.588+851C>T		intron_variant	Intron 5 of 11	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.405+851C>T		intron_variant	Intron 4 of 10		NP_001135995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9	c.588+851C>T		intron_variant	Intron 5 of 11	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000457197.2	c.405+851C>T		intron_variant	Intron 4 of 10	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36722 AN: 151908 Hom.: 4747 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.277

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

GnomAD4 genome AF: 0.242 AC: 36745 AN: 152026 Hom.: 4753 Cov.: 31 AF XY: 0.239 AC XY: 17789 AN XY: 74314

African (AFR) AF: 0.166 AC: 6870 AN: 41438

American (AMR) AF: 0.256 AC: 3913 AN: 15280

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

East Asian (EAS) AF: 0.130 AC: 672 AN: 5166

South Asian (SAS) AF: 0.215 AC: 1040 AN: 4834

European-Finnish (FIN) AF: 0.229 AC: 2418 AN: 10562

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

European-Non Finnish (NFE) AF: 0.290 AC: 19721 AN: 67962

Other (OTH) AF: 0.273 AC: 577 AN: 2112

Alfa AF: 0.279 Hom.: 10379

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	-0.90
CADD	Benign	0.68
DANN	Benign	0.45
PhyloP100		-0.93
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: rs1821777; hg19: chr12-66606228;