rs4251459

Variant names:

• chr12-43768763-T-C
• rs4251459
• NM_016123.4:c.161+491T>C

Variant summary

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

The NM_016123.4(IRAK4):​c.161+491T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,166 control chromosomes in the GnomAD database, including 6,510 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 0.23 (6510 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.675
• Publications: 9 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.161+491T>C		intron_variant	Intron 2 of 11	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.161+491T>C		intron_variant	Intron 2 of 11	1	NM_016123.4	ENSP00000479889.3

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35168 AN: 152048 Hom.: 6482 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0954

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.222

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

GnomAD4 genome AF: 0.232 AC: 35233 AN: 152166 Hom.: 6510 Cov.: 32 AF XY: 0.227 AC XY: 16913 AN XY: 74422

African (AFR) AF: 0.516 AC: 21380 AN: 41466

American (AMR) AF: 0.175 AC: 2676 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3468

East Asian (EAS) AF: 0.161 AC: 834 AN: 5170

South Asian (SAS) AF: 0.140 AC: 675 AN: 4822

European-Finnish (FIN) AF: 0.0954 AC: 1013 AN: 10618

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7400 AN: 68014

Other (OTH) AF: 0.220 AC: 464 AN: 2112

Alfa AF: 0.153 Hom.: 7114

Bravo AF: 0.249

Asia WGS AF: 0.185 AC: 643 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.80
PhyloP100		-0.68
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: rs4251459; hg19: chr12-44162566;