rs55944915

Variant names:

• chr12-43783708-G-A
• rs55944915
• NM_016123.4:c.1172G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (140 hom.)
• Consequence: IRAK4 NM_016123.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.74

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 464932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-43783708-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.1172G>A	p.Arg391His	missense_variant	Exon 10 of 12	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.1172G>A	p.Arg391His	missense_variant	Exon 10 of 12	1	NM_016123.4	ENSP00000479889.3

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1530 AN: 152088 Hom.: 9 Cov.: 32

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

GnomAD3 exomes AF: 0.0113 AC: 2818 AN: 249846 Hom.: 27 AF XY: 0.0120 AC XY: 1619 AN XY: 135086

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 SAS exome AF: 0.0163

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.: 27 AF XY: 0.0120 AC XY: 8691 AN XY: 722630

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.00546

Gnomad4 ASJ exome AF: 0.0358

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.00435

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0100 AC: 1528 AN: 152206 Hom.: 9 Cov.: 32 AF XY: 0.00993 AC XY: 739 AN XY: 74416

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00864

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.00444

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0143 Hom.: 19

Bravo AF: 0.00930

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0110 AC: 1339

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 67 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 26, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17878374, 30115681, 25764117) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

IRAK4-related disorder Benign:1

Nov 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	.;.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;.;D
MetaRNN	Benign	0.0085	T;T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.7	.;.;L;L
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.8	D;D;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Benign	0.077	T;T;T;T
Polyphen		1.0	.;.;D;D
Vest4		0.20
ClinPred		0.0099	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs55944915; hg19: chr12-44177511;