rs121908002

Positions:

chr12-43778238-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_016123.4(IRAK4):c.877C>T(p.Gln293*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,611,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 0 hom. )

Consequence

IRAK4
NM_016123.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.62

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-43778238-C-T is Pathogenic according to our data. Variant chr12-43778238-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-43778238-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK4	NM_016123.4 link	c.877C>T	p.Gln293*	stop_gained	8/12	ENST00000613694.5	NP_057207.2	Q9NWZ3-1Q69FE3B4E359B2RAP9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5 link	c.877C>T	p.Gln293*	stop_gained	8/12	1	NM_016123.4	ENSP00000479889.3		Q9NWZ3-1

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251346

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000466

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000676

AC:

987

AN:

1459592

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

484

AN XY:

726320

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000872

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000316

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000565

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 67

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Gln293*) in the IRAK4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IRAK4 are known to be pathogenic (PMID: 17893200, 21057262). This variant is present in population databases (rs121908002, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with IRAK4 deficiency (PMID: 12637671, 12925671, 19663824, 20621347, 25344726, 26472314). ClinVar contains an entry for this variant (Variation ID: 3839). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 2018	The IRAK4 c.877C>T (p.Gln293Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Gln293Ter variant has been identified in a total of 23 individuals with IRAK4 deficiency including 15 homozygotes and eight compound heterozygotes (Picard et al.2003; Picard et al. 2010; Andres et al. 2013; Frans et al. 2015). The p.Gln293Ter variant was absent from 160 healthy controls and is reported at a frequency of 0.000482 in the European (non-Finnish) population of the Genome Aggregation Database. Ku et al. (2007) used EBV-transformed B lymphocyte cell lines (B-EBVs) and SV40-transformed fibroblast cell lines (SV40-fibroblast) from a healthy control and IRAK4-deficient patients to demonstrate that cell lines bearing the p.Gln293Ter variant had low levels of detectable full length IRAK4 mRNA and no IRAK4 protein. In addition, B-EBVs bearing the p.Gln293Ter variant did not respond to TLR7 and TLR8 agonists as measured by TNF-alpha production, while SV40-fibroblasts bearing the p.Gln293Ter variant did not respond to IL1-beta as assessed by measuring IL6 production, together suggesting a complete IRAK4 deficiency and absence of IRAK4-dependent TIR signalling. Based on the collective evidence and the potential impact of stop-gained variants, the p.Gln293Ter variant is classified as pathogenic for IRAK4 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 28, 2022	ACMG codes: PVS1, PS3, PM2, PM3_VeryStrong, PP1_VeryStrong -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 27, 2020	This variant was identified as compound heterozygous with NM_016123.3:c.1148G>T. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	IRAK4: PM3:Very Strong, PVS1, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2023	Published functional studies demonstrate a damaging effect of the Q293X with undetectable mRNA levels in cells lines harboring this variant (Picard et al., 2003; Yamamot et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29431110, 17544092, 17114497, 24316379, 25344726, 25525159, 26472314, 29707745, 12637671, 21057262, 17893200, 29531937, 31526803, 31980526, 31589614, 32888943, 31345219, 33083971) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

IRAK4-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2023

The IRAK4 c.877C>T variant is predicted to result in premature protein termination (p.Gln293*). This variant has been reported to be causative for autosomal recessive IRAK4 deficiency (see for example - Picard et al. 2003. PubMed ID: 12637671; Picard et al. 2010. PubMed ID: 21057262; Lavine et al. 2007. PubMed ID: 17544092). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-44172041-C-T). Nonsense variants in IRAK4 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.87

Vest4

0.90

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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