12-43786492-G-A

Position:

chr12-43786492-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016123.4(IRAK4):c.1282G>A(p.Ala428Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,612,510 control chromosomes in the GnomAD database, including 10,368 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2177 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8191 hom. )

Consequence

IRAK4
NM_016123.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.863

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038244724).

BP6

Variant 12-43786492-G-A is Benign according to our data. Variant chr12-43786492-G-A is described in ClinVar as [Benign]. Clinvar id is 308732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-43786492-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK4	NM_016123.4 linkuse as main transcript	c.1282G>A	p.Ala428Thr	missense_variant	11/12	ENST00000613694.5	NP_057207.2	Q9NWZ3-1Q69FE3B4E359B2RAP9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5 linkuse as main transcript	c.1282G>A	p.Ala428Thr	missense_variant	11/12	1	NM_016123.4	ENSP00000479889.3		Q9NWZ3-1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22324

AN:

151884

Hom.:

2164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.271

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.0607

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.0921

Gnomad OTH

AF:

0.156

GnomAD3 exomes

AF:

0.114

AC:

28505

AN:

250834

Hom.:

1920

AF XY:

0.109

AC XY:

14835

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.271

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.113

Gnomad SAS exome

AF:

0.109

Gnomad FIN exome

AF:

0.0630

Gnomad NFE exome

AF:

0.0932

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0996

AC:

145462

AN:

1460508

Hom.:

8191

Cov.:

AF XY:

0.0990

AC XY:

71950

AN XY:

726566

show subpopulations

Gnomad4 AFR exome

AF:

0.279

Gnomad4 AMR exome

AF:

0.134

Gnomad4 ASJ exome

AF:

0.159

Gnomad4 EAS exome

AF:

0.0898

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.0670

Gnomad4 NFE exome

AF:

0.0916

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.147

AC:

22362

AN:

152002

Hom.:

2177

Cov.:

AF XY:

0.144

AC XY:

10706

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.272

Gnomad4 AMR

AF:

0.140

Gnomad4 ASJ

AF:

0.155

Gnomad4 EAS

AF:

0.105

Gnomad4 SAS

AF:

0.117

Gnomad4 FIN

AF:

0.0607

Gnomad4 NFE

AF:

0.0921

Gnomad4 OTH

AF:

0.154

Alfa

AF:

0.107

Hom.:

2543

Bravo

AF:

0.158

TwinsUK

AF:

0.0841

AC:

312

ALSPAC

AF:

0.0931

AC:

359

ESP6500AA

AF:

0.272

AC:

1200

ESP6500EA

AF:

0.0986

AC:

847

ExAC

AF:

0.115

AC:

13993

Asia WGS

AF:

0.126

AC:

437

AN:

3476

EpiCase

AF:

0.0955

EpiControl

AF:

0.0975

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper claims increased risk of gram positive infection -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported. -

Immunodeficiency 67

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21576904) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.2

DANN

Benign

0.62

DEOGEN2

Benign

0.17

.;.;T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.62

.;T;.;T

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;L;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.47

N;N;.;N

REVEL

Benign

0.056

Sift

Benign

0.62

T;T;.;T

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.0

.;.;B;B

Vest4

0.028

ClinPred

0.0026

GERP RS

-0.29

Varity_R

0.060

gMVP

0.090

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over