Genetic Variant IRAK3:p.Ala30Pro (chr12-66189387-G-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_007199.3(IRAK3):c.88G>C(p.Ala30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,375,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0850

Publications

0 publications found

Variant links:

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

IRAK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3868168).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3 link	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2	Q9Y616-1
IRAK3	NM_001142523.2 link	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 11		NP_001135995.1	Q9Y616-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRAK3	ENST00000261233.9 link	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4	Q9Y616-1
IRAK3	ENST00000545837.1 link	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 2	1		ENSP00000441321.1	F5GYN6
IRAK3	ENST00000457197.2 link	c.88G>C	p.Ala30Pro	missense_variant	Exon 1 of 11	2		ENSP00000409852.2	Q9Y616-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000436

AC:

AN:

1375578

Hom.:

Cov.:

AF XY:

0.00000442

AC XY:

AN XY:

678464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30900

American (AMR)

AF:

0.00

AC:

AN:

35442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24866

East Asian (EAS)

AF:

0.00

AC:

AN:

35444

South Asian (SAS)

AF:

0.00

AC:

AN:

78844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.00000558

AC:

AN:

1075268

Other (OTH)

AF:

0.00

AC:

AN:

57334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.88G>C (p.A30P) alteration is located in exon 1 (coding exon 1) of the IRAK3 gene. This alteration results from a G to C substitution at nucleotide position 88, causing the alanine (A) at amino acid position 30 to be replaced by a proline (P). 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

Pathogenic

0.64

BayesDel_addAF

Benign

0.0024

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.67

T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.4

L;.;L

PhyloP100

-0.085

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.1

N;D;N

REVEL

Benign

0.22

Sift

Benign

0.18

T;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.78

P;D;D

Vest4

0.16

MutPred

0.52

Gain of catalytic residue at E27 (P = 0.0025);Gain of catalytic residue at E27 (P = 0.0025);Gain of catalytic residue at E27 (P = 0.0025);

MVP

0.97

MPC

0.12

ClinPred

0.38

GERP RS

1.2

PromoterAI

0.20

Neutral

(source)

Varity_R

0.27

gMVP

0.60

Mutation Taster

=64/36

polymorphism

(source)

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

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12-66189387-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over