rs1152888

Positions:

• chr12-66211448-A-C
• chr12-66211448-A-G
• chr12-66211448-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007199.3(IRAK3):​c.439A>C​(p.Ile147Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I147V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRAK3 NM_007199.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.420

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067384034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.439A>C	p.Ile147Leu	missense_variant, splice_region_variant	5/12	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.256A>C	p.Ile86Leu	missense_variant, splice_region_variant	4/11		NP_001135995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9	c.439A>C	p.Ile147Leu	missense_variant, splice_region_variant	5/12	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000457197.2	c.256A>C	p.Ile86Leu	missense_variant, splice_region_variant	4/11	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250616 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.99
DANN	Benign	0.82
DEOGEN2	Benign	0.049	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.029
Sift	Benign	0.75	T;T
Sift4G	Uncertain	0.027	D;D
Polyphen		0.014	B;B
Vest4		0.15
MutPred		0.38		Gain of catalytic residue at N143 (P = 0.0012);.;
MVP		0.75
MPC		0.023
ClinPred		0.022	T
GERP RS		0.74
Varity_R		0.042
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1152888; hg19: chr12-66605228;