Genetic Variant IRAK3:c.381+99C>T (chr12-66209619-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007199.3(IRAK3):c.381+99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 804,198 control chromosomes in the GnomAD database, including 26,649 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4259 hom., cov: 32)

Exomes 𝑓: 0.25 ( 22390 hom. )

Consequence

IRAK3
NM_007199.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.765

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3 link	c.381+99C>T		intron_variant	Intron 3 of 11	ENST00000261233.9	NP_009130.2	Q9Y616-1
IRAK3	NM_001142523.2 link	c.198+99C>T		intron_variant	Intron 2 of 10		NP_001135995.1	Q9Y616-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9 link	c.381+99C>T		intron_variant	Intron 3 of 11	1	NM_007199.3	ENSP00000261233.4		Q9Y616-1
IRAK3	ENST00000457197.2 link	c.198+99C>T		intron_variant	Intron 2 of 10	2		ENSP00000409852.2		Q9Y616-2

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33432

AN:

151888

Hom.:

4256

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0904

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.266

GnomAD4 exome

AF:

0.255

AC:

166235

AN:

652192

Hom.:

22390

AF XY:

0.256

AC XY:

90234

AN XY:

351968

show subpopulations

African (AFR)

AF:

0.0931

AC:

1677

AN:

18018

American (AMR)

AF:

0.208

AC:

8518

AN:

40908

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

5944

AN:

20706

East Asian (EAS)

AF:

0.136

AC:

4834

AN:

35536

South Asian (SAS)

AF:

0.215

AC:

14602

AN:

67956

European-Finnish (FIN)

AF:

0.237

AC:

11418

AN:

48226

Middle Eastern (MID)

AF:

0.308

AC:

1280

AN:

4152

European-Non Finnish (NFE)

AF:

0.285

AC:

109398

AN:

383256

Other (OTH)

AF:

0.256

AC:

8564

AN:

33434

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

5809

11617

17426

23234

29043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1106

2212

3318

4424

5530

<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:

0.220

AC:

33430

AN:

152006

Hom.:

4259

Cov.:

AF XY:

0.219

AC XY:

16233

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.0900

AC:

3732

AN:

41476

American (AMR)

AF:

0.248

AC:

3791

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

1003

AN:

3468

East Asian (EAS)

AF:

0.131

AC:

677

AN:

5172

South Asian (SAS)

AF:

0.213

AC:

1028

AN:

4816

European-Finnish (FIN)

AF:

0.231

AC:

2426

AN:

10518

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.290

AC:

19690

AN:

67950

Other (OTH)

AF:

0.263

AC:

554

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1312

2624

3936

5248

6560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.245

Hom.:

644

Bravo

AF:

0.215

Asia WGS

AF:

0.163

AC:

566

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.45

(source)

DANN

Benign

0.42

PhyloP100

-0.77

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over