Genetic Variant ENST00000545837.1:c.206A>G (chr12-66196952-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000545837.1(IRAK3):c.206A>G(p.Tyr69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,535,268 control chromosomes in the GnomAD database, including 2,335 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.071 ( 1244 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 1091 hom. )

Consequence

IRAK3
ENST00000545837.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.80

Publications

3 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 (MetaRNN=0.0020825267).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3 link	c.134-6759A>G		intron_variant	Intron 1 of 11	ENST00000261233.9	NP_009130.2	Q9Y616-1
IRAK3	NM_001142523.2 link	c.133+7520A>G		intron_variant	Intron 1 of 10		NP_001135995.1	Q9Y616-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRAK3	ENST00000545837.1 link	c.206A>G	p.Tyr69Cys	missense_variant	Exon 2 of 2	1		ENSP00000441321.1	F5GYN6
IRAK3	ENST00000261233.9 link	c.134-6759A>G		intron_variant	Intron 1 of 11	1	NM_007199.3	ENSP00000261233.4	Q9Y616-1
IRAK3	ENST00000457197.2 link	c.133+7520A>G		intron_variant	Intron 1 of 10	2		ENSP00000409852.2	Q9Y616-2

Frequencies

GnomAD3 genomes

AF:

0.0709

AC:

10782

AN:

152120

Hom.:

1243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.0584

GnomAD2 exomes

AF:

0.0147

AC:

1967

AN:

133466

AF XY:

0.0115

show subpopulations

Gnomad AFR exome

AF:

0.237

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00771

AC:

10669

AN:

1383030

Hom.:

1091

Cov.:

AF XY:

0.00684

AC XY:

4671

AN XY:

682422

show subpopulations

African (AFR)

AF:

0.249

AC:

7848

AN:

31490

American (AMR)

AF:

0.0165

AC:

588

AN:

35536

Ashkenazi Jewish (ASJ)

AF:

0.00135

AC:

AN:

25144

East Asian (EAS)

AF:

0.00

AC:

AN:

35682

South Asian (SAS)

AF:

0.000772

AC:

AN:

79036

European-Finnish (FIN)

AF:

0.0000590

AC:

AN:

33876

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.000942

AC:

1016

AN:

1078714

Other (OTH)

AF:

0.0181

AC:

1045

AN:

57860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

446

893

1339

1786

2232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.0709

AC:

10797

AN:

152238

Hom.:

1244

Cov.:

AF XY:

0.0679

AC XY:

5055

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.244

AC:

10128

AN:

41480

American (AMR)

AF:

0.0296

AC:

453

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68028

Other (OTH)

AF:

0.0578

AC:

122

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

420

840

1261

1681

2101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0239

Hom.:

445

Bravo

AF:

0.0822

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0115

AC:

172

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

PhyloP100

1.8

PROVEAN

Uncertain

-4.4

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.13

ClinPred

0.088

GERP RS

4.4

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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