Genetic Variant NM_007199.3:c.*525G>C (chr12-66248696-G-C) – 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.*525G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 152,872 control chromosomes in the GnomAD database, including 332 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 0.056 ( 332 hom., cov: 32)

Exomes 𝑓: 0.068 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.788

Publications

10 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=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0811 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007199.3. 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.*525G>C		3_prime_UTR	Exon 12 of 12	NP_009130.2
	IRAK3	NM_001142523.2		c.*525G>C		3_prime_UTR	Exon 11 of 11	NP_001135995.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IRAK3	ENST00000261233.9	TSL:1 MANE Select	c.*525G>C	3_prime_UTR	Exon 12 of 12	ENSP00000261233.4
IRAK3	ENST00000854785.1		c.*525G>C	3_prime_UTR	Exon 12 of 12	ENSP00000524844.1
IRAK3	ENST00000947373.1		c.*525G>C	downstream_gene	N/A	ENSP00000617432.1

Frequencies

GnomAD3 genomes

AF:

0.0561

AC:

8526

AN:

152108

Hom.:

333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.0974

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0689

Gnomad FIN

AF:

0.0680

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0829

Gnomad OTH

AF:

0.0560

GnomAD4 exome

AF:

0.0681

AC:

AN:

646

Hom.:

Cov.:

AF XY:

0.0533

AC XY:

AN XY:

338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0217

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.0667

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0758

AC:

AN:

462

Other (OTH)

AF:

0.125

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0560

AC:

8522

AN:

152226

Hom.:

332

Cov.:

AF XY:

0.0557

AC XY:

4144

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0143

AC:

595

AN:

41538

American (AMR)

AF:

0.0466

AC:

713

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0974

AC:

338

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0687

AC:

332

AN:

4832

European-Finnish (FIN)

AF:

0.0680

AC:

720

AN:

10586

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0829

AC:

5636

AN:

68016

Other (OTH)

AF:

0.0554

AC:

117

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

427

854

1280

1707

2134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0662

Hom.:

Bravo

AF:

0.0527

Asia WGS

AF:

0.0330

AC:

113

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.46

(source)

DANN

Benign

0.60

PhyloP100

-0.79

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over