12-66224436-A-G

Variant names:

• chr12-66224436-A-G
• rs1624395
• NM_007199.3:c.654-2287A>G

Variant summary

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

The NM_007199.3(IRAK3):​c.654-2287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 152,016 control chromosomes in the GnomAD database, including 30,415 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 0.63 (30415 hom., cov: 31)
• Consequence: IRAK3 NM_007199.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.713
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007199.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK3	NM_007199.3	MANE Select	c.654-2287A>G		intron	N/A	NP_009130.2
	IRAK3	NM_001142523.2		c.471-2287A>G		intron	N/A	NP_001135995.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK3	ENST00000261233.9	TSL:1 MANE Select	c.654-2287A>G		intron	N/A	ENSP00000261233.4
	IRAK3	ENST00000457197.2	TSL:2	c.471-2287A>G		intron	N/A	ENSP00000409852.2

Frequencies

GnomAD3 genomes AF: 0.629 AC: 95561 AN: 151900 Hom.: 30381 Cov.: 31

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.608

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

GnomAD4 genome AF: 0.629 AC: 95642 AN: 152016 Hom.: 30415 Cov.: 31 AF XY: 0.631 AC XY: 46893 AN XY: 74306

African (AFR) AF: 0.562 AC: 23285 AN: 41438

American (AMR) AF: 0.681 AC: 10389 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2261 AN: 3468

East Asian (EAS) AF: 0.469 AC: 2428 AN: 5176

South Asian (SAS) AF: 0.662 AC: 3191 AN: 4822

European-Finnish (FIN) AF: 0.708 AC: 7485 AN: 10572

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44796 AN: 67962

Other (OTH) AF: 0.612 AC: 1290 AN: 2108

Alfa AF: 0.648 Hom.: 8901

Bravo AF: 0.623

Asia WGS AF: 0.574 AC: 2000 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.34
DANN	Benign	0.77
PhyloP100		-0.71
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: rs1624395; hg19: chr12-66618216;