chr12-43786492-G-A

Variant names:

• chr12-43786492-G-A
• rs4251545
• NM_016123.4:c.1282G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.863
• Publications: 58 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 308732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	NM_016123.4	MANE Select	c.1282G>A	p.Ala428Thr	missense	Exon 11 of 12	NP_057207.2
	IRAK4	NM_001114182.3		c.1282G>A	p.Ala428Thr	missense	Exon 12 of 13	NP_001107654.1
	IRAK4	NM_001351345.2		c.1282G>A	p.Ala428Thr	missense	Exon 12 of 13	NP_001338274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.1282G>A	p.Ala428Thr	missense	Exon 11 of 12	ENSP00000479889.3
	IRAK4	ENST00000551736.5	TSL:1	c.1282G>A	p.Ala428Thr	missense	Exon 12 of 13	ENSP00000446490.1
	IRAK4	ENST00000547101.5	TSL:1	n.*1184G>A		non_coding_transcript_exon	Exon 12 of 13	ENSP00000449317.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22324 AN: 151884 Hom.: 2164 Cov.: 32

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

GnomAD2 exomes AF: 0.114 AC: 28505 AN: 250834 AF XY: 0.109

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 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.: 31 AF XY: 0.0990 AC XY: 71950 AN XY: 726566

African (AFR) AF: 0.279 AC: 9331 AN: 33402

American (AMR) AF: 0.134 AC: 5965 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4150 AN: 26100

East Asian (EAS) AF: 0.0898 AC: 3556 AN: 39598

South Asian (SAS) AF: 0.106 AC: 9128 AN: 86028

European-Finnish (FIN) AF: 0.0670 AC: 3576 AN: 53394

Middle Eastern (MID) AF: 0.167 AC: 963 AN: 5758

European-Non Finnish (NFE) AF: 0.0916 AC: 101764 AN: 1111264

Other (OTH) AF: 0.117 AC: 7029 AN: 60330

GnomAD4 genome AF: 0.147 AC: 22362 AN: 152002 Hom.: 2177 Cov.: 32 AF XY: 0.144 AC XY: 10706 AN XY: 74300

African (AFR) AF: 0.272 AC: 11271 AN: 41444

American (AMR) AF: 0.140 AC: 2132 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 538 AN: 3466

East Asian (EAS) AF: 0.105 AC: 542 AN: 5170

South Asian (SAS) AF: 0.117 AC: 563 AN: 4830

European-Finnish (FIN) AF: 0.0607 AC: 639 AN: 10526

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.0921 AC: 6260 AN: 67990

Other (OTH) AF: 0.154 AC: 324 AN: 2110

Alfa AF: 0.112 Hom.: 5256

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

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 06, 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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21576904)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.2
DANN	Benign	0.62
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.86
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.056
Sift	Benign	0.62	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.028
ClinPred		0.0026	T
GERP RS		-0.29
Varity_R		0.060
gMVP		0.090
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4251545; hg19: chr12-44180295; COSMIC: COSV71210481; COSMIC: COSV71210481;