chr12-66211448-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_007199.3(IRAK3):c.439A>G(p.Ile147Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 1,589,414 control chromosomes in the GnomAD database, including 652,620 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.79 ( 50526 hom., cov: 32)

Exomes 𝑓: 0.91 ( 602094 hom. )

Consequence

IRAK3
NM_007199.3 missense, splice_region

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.420

Publications

49 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.8947065E-7).

BP6

Variant 12-66211448-A-G is Benign according to our data. Variant chr12-66211448-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059815.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3 link	c.439A>G	p.Ile147Val	missense_variant, splice_region_variant	Exon 5 of 12	ENST00000261233.9	NP_009130.2	Q9Y616-1
IRAK3	NM_001142523.2 link	c.256A>G	p.Ile86Val	missense_variant, splice_region_variant	Exon 4 of 11		NP_001135995.1	Q9Y616-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9 link	c.439A>G	p.Ile147Val	missense_variant, splice_region_variant	Exon 5 of 12	1	NM_007199.3	ENSP00000261233.4		Q9Y616-1
IRAK3	ENST00000457197.2 link	c.256A>G	p.Ile86Val	missense_variant, splice_region_variant	Exon 4 of 11	2		ENSP00000409852.2		Q9Y616-2

Frequencies

GnomAD3 genomes

AF:

0.790

AC:

120057

AN:

152054

Hom.:

50509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.480

Gnomad AMI

AF:

0.838

Gnomad AMR

AF:

0.897

Gnomad ASJ

AF:

0.937

Gnomad EAS

AF:

0.600

Gnomad SAS

AF:

0.869

Gnomad FIN

AF:

0.914

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.933

Gnomad OTH

AF:

0.827

GnomAD2 exomes

AF:

0.872

AC:

218441

AN:

250616

AF XY:

0.879

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.945

Gnomad ASJ exome

AF:

0.935

Gnomad EAS exome

AF:

0.597

Gnomad FIN exome

AF:

0.911

Gnomad NFE exome

AF:

0.931

Gnomad OTH exome

AF:

0.896

GnomAD4 exome

AF:

0.911

AC:

1308715

AN:

1437242

Hom.:

602094

Cov.:

AF XY:

0.911

AC XY:

652923

AN XY:

716676

show subpopulations

African (AFR)

AF:

0.467

AC:

15461

AN:

33072

American (AMR)

AF:

0.938

AC:

41845

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.938

AC:

24337

AN:

25954

East Asian (EAS)

AF:

0.592

AC:

23376

AN:

39482

South Asian (SAS)

AF:

0.888

AC:

76065

AN:

85644

European-Finnish (FIN)

AF:

0.911

AC:

48609

AN:

53336

Middle Eastern (MID)

AF:

0.880

AC:

4977

AN:

5656

European-Non Finnish (NFE)

AF:

0.937

AC:

1021557

AN:

1089876

Other (OTH)

AF:

0.881

AC:

52488

AN:

59600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

4651

9303

13954

18606

23257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20874

41748

62622

83496

104370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.789

AC:

120113

AN:

152172

Hom.:

50526

Cov.:

AF XY:

0.791

AC XY:

58830

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.480

AC:

19919

AN:

41462

American (AMR)

AF:

0.897

AC:

13729

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.937

AC:

3253

AN:

3470

East Asian (EAS)

AF:

0.600

AC:

3099

AN:

5166

South Asian (SAS)

AF:

0.869

AC:

4196

AN:

4830

European-Finnish (FIN)

AF:

0.914

AC:

9696

AN:

10604

Middle Eastern (MID)

AF:

0.881

AC:

259

AN:

294

European-Non Finnish (NFE)

AF:

0.933

AC:

63446

AN:

68020

Other (OTH)

AF:

0.828

AC:

1752

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1009

2017

3026

4034

5043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.888

Hom.:

273785

Bravo

AF:

0.773

TwinsUK

AF:

0.944

AC:

3502

ALSPAC

AF:

0.937

AC:

3611

ESP6500AA

AF:

0.493

AC:

2170

ESP6500EA

AF:

0.933

AC:

8022

ExAC

AF:

0.862

AC:

104622

Asia WGS

AF:

0.726

AC:

2527

AN:

3478

EpiCase

AF:

0.933

EpiControl

AF:

0.926

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IRAK3-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.49

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.050

T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

6.9e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.

PhyloP100

-0.42

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.033

Sift

Benign

0.61

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0010

B;B

Vest4

0.027

MPC

0.021

ClinPred

0.0014

GERP RS

0.74

Varity_R

0.028

gMVP

0.13

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over