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:

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new If you want to explore the variant's impact on the transcript ENST00000545837.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000545837.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK3	NM_007199.3	MANE Select	c.134-6759A>G		intron	N/A	NP_009130.2	Q9Y616-1
	IRAK3	NM_001142523.2		c.133+7520A>G		intron	N/A	NP_001135995.1	Q9Y616-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAK3	ENST00000545837.1	TSL:1	c.206A>G	p.Tyr69Cys	missense	Exon 2 of 2	ENSP00000441321.1	F5GYN6
IRAK3	ENST00000261233.9	TSL:1 MANE Select	c.134-6759A>G		intron	N/A	ENSP00000261233.4	Q9Y616-1
IRAK3	ENST00000854785.1		c.134-6762A>G		intron	N/A	ENSP00000524844.1

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

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over