Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016123.4(IRAK4):c.1172G>A(p.Arg391His) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,603,352 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 32)

Exomes 𝑓: 0.012 ( 140 hom. )

Consequence

IRAK4
NM_016123.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.74

Publications

19 publications found

Variant links:

Genes affected

IRAK4 (HGNC:17967): (interleukin 1 receptor associated kinase 4) This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

IRAK4 Gene-Disease associations (from GenCC):

immunodeficiency 67
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

IRAK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008516699).

BP6

Variant 12-43783708-G-A is Benign according to our data. Variant chr12-43783708-G-A is described in ClinVar as Benign. ClinVar VariationId is 464932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.01 (1528/152206) while in subpopulation NFE AF = 0.0148 (1006/68010). AF 95% confidence interval is 0.014. There are 9 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IRAK4	NM_016123.4	MANE Select	c.1172G>A	p.Arg391His	missense	Exon 10 of 12	NP_057207.2
IRAK4	NM_001114182.3		c.1172G>A	p.Arg391His	missense	Exon 11 of 13	NP_001107654.1
IRAK4	NM_001351345.2		c.1172G>A	p.Arg391His	missense	Exon 11 of 13	NP_001338274.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.1172G>A	p.Arg391His	missense	Exon 10 of 12	ENSP00000479889.3
IRAK4	ENST00000551736.5	TSL:1	c.1172G>A	p.Arg391His	missense	Exon 11 of 13	ENSP00000446490.1
IRAK4	ENST00000547101.5	TSL:1	n.*1074G>A		non_coding_transcript_exon	Exon 11 of 13	ENSP00000449317.1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1530

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.00865

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.00444

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0113

AC:

2818

AN:

249846

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00242

Gnomad AMR exome

AF:

0.00517

Gnomad ASJ exome

AF:

0.0359

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00444

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0116

AC:

16785

AN:

1451146

Hom.:

140

Cov.:

AF XY:

0.0120

AC XY:

8691

AN XY:

722630

show subpopulations

African (AFR)

AF:

0.00165

AC:

AN:

33286

American (AMR)

AF:

0.00546

AC:

244

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.0358

AC:

933

AN:

26044

East Asian (EAS)

AF:

0.000101

AC:

AN:

39626

South Asian (SAS)

AF:

0.0157

AC:

1351

AN:

85954

European-Finnish (FIN)

AF:

0.00435

AC:

231

AN:

53056

Middle Eastern (MID)

AF:

0.0266

AC:

153

AN:

5742

European-Non Finnish (NFE)

AF:

0.0119

AC:

13088

AN:

1102794

Other (OTH)

AF:

0.0121

AC:

726

AN:

59992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

707

1414

2122

2829

3536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.0100

AC:

1528

AN:

152206

Hom.:

Cov.:

AF XY:

0.00993

AC XY:

739

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41528

American (AMR)

AF:

0.00864

AC:

132

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.0129

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00444

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1006

AN:

68010

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0132

Hom.:

Bravo

AF:

0.00930

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.0110

AC:

1339

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0159

EpiControl

AF:

0.0133

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 67 (2)

not provided (2)

IRAK4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0085

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.7

PhyloP100

5.7

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

Sift4G

Benign

0.077

Polyphen

1.0

Vest4

0.20

ClinPred

0.0099

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.60

Mutation Taster

=99/1

polymorphism

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over