chr12-43785776-G-T

Variant names:

• chr12-43785776-G-T
• rs4251540
• NM_016123.4:c.1189-623G>T

Variant summary

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

The NM_016123.4(IRAK4):​c.1189-623G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 151,466 control chromosomes in the GnomAD database, including 2,165 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 0.15 (2165 hom., cov: 31)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.515
• Publications: 8 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.1189-623G>T		intron_variant	Intron 10 of 11	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.1189-623G>T		intron_variant	Intron 10 of 11	1	NM_016123.4	ENSP00000479889.3

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22265 AN: 151354 Hom.: 2151 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0609

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.147 AC: 22303 AN: 151466 Hom.: 2165 Cov.: 31 AF XY: 0.144 AC XY: 10685 AN XY: 73984

African (AFR) AF: 0.272 AC: 11238 AN: 41246

American (AMR) AF: 0.140 AC: 2127 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 535 AN: 3468

East Asian (EAS) AF: 0.105 AC: 541 AN: 5150

South Asian (SAS) AF: 0.117 AC: 564 AN: 4806

European-Finnish (FIN) AF: 0.0609 AC: 632 AN: 10382

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.0921 AC: 6252 AN: 67904

Other (OTH) AF: 0.153 AC: 322 AN: 2108

Alfa AF: 0.0928 Hom.: 206

Bravo AF: 0.158

Asia WGS AF: 0.125 AC: 436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.75
DANN	Benign	0.35
PhyloP100		-0.52
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: rs4251540; hg19: chr12-44179579;