rs2052376166

Variant names:

• chr12-66189387-G-A
• rs2052376166
• NM_007199.3:c.88G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-66189387-G-A
• chr12-66189387-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007199.3(IRAK3):​c.88G>A​(p.Ala30Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. A30P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: IRAK3 NM_007199.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17241919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.88G>A	p.Ala30Thr	missense_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.88G>A	p.Ala30Thr	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.88G>A	p.Ala30Thr	missense_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000545837.1	c.88G>A	p.Ala30Thr	missense_variant	Exon 1 of 2	1		ENSP00000441321.1
IRAK3	ENST00000457197.2	c.88G>A	p.Ala30Thr	missense_variant	Exon 1 of 11	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1375578 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 678464

African (AFR) AF: 0.00 AC: 0 AN: 30900

American (AMR) AF: 0.00 AC: 0 AN: 35442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24866

East Asian (EAS) AF: 0.00 AC: 0 AN: 35444

South Asian (SAS) AF: 0.00 AC: 0 AN: 78844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4098

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1075268

Other (OTH) AF: 0.00 AC: 0 AN: 57334

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L;.;L
PhyloP100		-0.085
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.58	N;D;N
REVEL	Benign	0.10
Sift	Benign	0.35	T;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.050	B;B;B
Vest4		0.042
MutPred		0.52		Gain of catalytic residue at E27 (P = 0.0019);Gain of catalytic residue at E27 (P = 0.0019);Gain of catalytic residue at E27 (P = 0.0019);
MVP		0.95
MPC		0.023
ClinPred		0.079	T
GERP RS		1.2
PromoterAI		0.030	Neutral
Varity_R		0.056
gMVP		0.24
Mutation Taster		=69/31	polymorphism

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: rs2052376166; hg19: chr12-66583167;