chr12-66189384-T-G

Variant names:

• chr12-66189384-T-G
• NM_007199.3:c.85T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007199.3(IRAK3):​c.85T>G​(p.Cys29Gly) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRAK3 NM_007199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.85T>G	p.Cys29Gly	missense_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.85T>G	p.Cys29Gly	missense_variant	Exon 1 of 11		NP_001135995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9	c.85T>G	p.Cys29Gly	missense_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000545837.1	c.85T>G	p.Cys29Gly	missense_variant	Exon 1 of 2	1		ENSP00000441321.1
IRAK3	ENST00000457197.2	c.85T>G	p.Cys29Gly	missense_variant	Exon 1 of 11	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.85T>G (p.C29G) alteration is located in exon 1 (coding exon 1) of the IRAK3 gene. This alteration results from a T to G substitution at nucleotide position 85, causing the cysteine (C) at amino acid position 29 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.69
DEOGEN2	Uncertain	0.65	D;.;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.4	M;.;M
PhyloP100		2.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.072	T;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.53
MutPred		0.78		Gain of catalytic residue at E27 (P = 0.0026);Gain of catalytic residue at E27 (P = 0.0026);Gain of catalytic residue at E27 (P = 0.0026);
MVP		0.83
MPC		0.19
ClinPred		0.99	D
GERP RS		3.4
PromoterAI		0.042	Neutral
Varity_R		0.51
gMVP		0.54

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

hg19: chr12-66583164;