12-66189393-C-A

Position:

• chr12-66189393-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007199.3(IRAK3):​c.94C>A​(p.Leu32Met) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRAK3 NM_007199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.875

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18696204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK3	NM_007199.3	c.94C>A	p.Leu32Met	missense_variant	1/12	ENST00000261233.9
IRAK3	NM_001142523.2	c.94C>A	p.Leu32Met	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK3	ENST00000261233.9	c.94C>A	p.Leu32Met	missense_variant	1/12	1	NM_007199.3	P1
IRAK3	ENST00000545837.1	c.94C>A	p.Leu32Met	missense_variant	1/2	1
IRAK3	ENST00000457197.2	c.94C>A	p.Leu32Met	missense_variant	1/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.95	L;.;L
MutationTaster	Benign	0.93	D;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.85	N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.13	B;D;D
Vest4		0.22
MutPred		0.54		Gain of catalytic residue at L32 (P = 0);Gain of catalytic residue at L32 (P = 0);Gain of catalytic residue at L32 (P = 0);
MVP		0.85
MPC		0.025
ClinPred		0.22	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.27

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: rs1555201779; hg19: chr12-66583173;