chr12-43774562-A-G

Variant names:

• chr12-43774562-A-G
• rs4251481
• NM_016123.4:c.716+533A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016123.4(IRAK4):​c.716+533A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 152,264 control chromosomes in the GnomAD database, including 1,073 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.078 (1073 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.716+533A>G		intron_variant	Intron 6 of 11	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.716+533A>G		intron_variant	Intron 6 of 11	1	NM_016123.4	ENSP00000479889.3

Frequencies

GnomAD3 genomes AF: 0.0777 AC: 11824 AN: 152146 Hom.: 1074 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.0564

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0641

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0778 AC: 11840 AN: 152264 Hom.: 1073 Cov.: 32 AF XY: 0.0766 AC XY: 5707 AN XY: 74472

African (AFR) AF: 0.221 AC: 9166 AN: 41522

American (AMR) AF: 0.0311 AC: 475 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3468

East Asian (EAS) AF: 0.0569 AC: 295 AN: 5182

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4834

European-Finnish (FIN) AF: 0.0345 AC: 366 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1130 AN: 68032

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0340 Hom.: 233

Bravo AF: 0.0846

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.2
DANN	Benign	0.70
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4251481; hg19: chr12-44168365; COSMIC: COSV71210261; COSMIC: COSV71210261;