Genetic Variant IRAK3:p.Met1? (chr12-66189300-A-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PVS1_SupportingBP6_ModerateBS2

The NM_007199.3(IRAK3):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,536,240 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00040 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

IRAK3
NM_007199.3 start_lost

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.80

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 93 codons. Genomic position: 66203854. Lost 0.155 part of the original CDS.

BP6

Variant 12-66189300-A-G is Benign according to our data. Variant chr12-66189300-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 736195.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 61 AD gene.

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.1A>G	p.Met1?	start_lost	Exon 1 of 12	NP_009130.2	Q9Y616-1
	IRAK3	NM_001142523.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 11	NP_001135995.1	Q9Y616-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAK3	ENST00000261233.9	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000261233.4	Q9Y616-1
IRAK3	ENST00000545837.1	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 2	ENSP00000441321.1	F5GYN6
IRAK3	ENST00000854785.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000524844.1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000204

AC:

AN:

132448

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00346

Gnomad NFE exome

AF:

0.000140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000190

AC:

263

AN:

1383928

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

126

AN XY:

683186

show subpopulations

African (AFR)

AF:

0.0000315

AC:

AN:

31698

American (AMR)

AF:

0.00

AC:

AN:

35894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25090

East Asian (EAS)

AF:

0.0000278

AC:

AN:

36034

South Asian (SAS)

AF:

0.00

AC:

AN:

79410

European-Finnish (FIN)

AF:

0.00417

AC:

140

AN:

33598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4742

European-Non Finnish (NFE)

AF:

0.0000954

AC:

103

AN:

1079698

Other (OTH)

AF:

0.000312

AC:

AN:

57764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000400

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41582

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000794

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000345

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.11

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.85

PhyloP100

1.8

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.12

Vest4

0.64

MutPred

0.98

Gain of catalytic residue at C5 (P = 0.0011)

MVP

0.83

ClinPred

0.40

GERP RS

3.3

PromoterAI

-0.40

Neutral

(source)

Varity_R

0.95

gMVP

0.32

Mutation Taster

=21/179

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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