12-66189304-C-G

Variant names:

Variant summary

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

The NM_007199.3(IRAK3):c.5C>G(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000716 in 1,536,134 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.632

Publications

1 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:

Genome browser will be placed here

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=0.3333941).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2	Q9Y616-1
IRAK3	NM_001142523.2 link	c.5C>G	p.Ala2Gly	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.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4	Q9Y616-1
IRAK3	ENST00000545837.1 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 2	1		ENSP00000441321.1	F5GYN6
IRAK3	ENST00000457197.2 link	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 11	2		ENSP00000409852.2	Q9Y616-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000289

AC:

AN:

1383824

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31690

American (AMR)

AF:

0.00

AC:

AN:

35900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25072

East Asian (EAS)

AF:

0.00

AC:

AN:

36028

South Asian (SAS)

AF:

0.00

AC:

AN:

79386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4732

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079644

Other (OTH)

AF:

0.0000692

AC:

AN:

57766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.000457

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5C>G (p.A2G) alteration is located in exon 1 (coding exon 1) of the IRAK3 gene. This alteration results from a C to G substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 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

Benign

0.11

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.084

T;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.54

T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.46

N;.;N

PhyloP100

0.63

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.7

N;D;N

REVEL

Benign

0.14

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.97

D;D;D

Vest4

0.092

MutPred

0.31

Gain of catalytic residue at G3 (P = 0);Gain of catalytic residue at G3 (P = 0);Gain of catalytic residue at G3 (P = 0);

MVP

0.83

MPC

0.022

ClinPred

0.58

GERP RS

2.7

PromoterAI

-0.31

Neutral

(source)

Varity_R

0.31

gMVP

0.22

Mutation Taster

=87/13

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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12-66189304-C-G

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