12-43776079-G-T

Variant names:

• chr12-43776079-G-T
• rs4251487
• NM_016123.4:c.717-1551G>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.717-1551G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 151,578 control chromosomes in the GnomAD database, including 1,319 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 0.11 (1319 hom., cov: 30)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 5 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 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.717-1551G>T		intron	N/A	NP_057207.2
	IRAK4	NM_001114182.3		c.717-1551G>T		intron	N/A	NP_001107654.1
	IRAK4	NM_001351345.2		c.717-1551G>T		intron	N/A	NP_001338274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.717-1551G>T		intron	N/A	ENSP00000479889.3
	IRAK4	ENST00000551736.5	TSL:1	c.717-1551G>T		intron	N/A	ENSP00000446490.1
	IRAK4	ENST00000547101.5	TSL:1	n.*619-1551G>T		intron	N/A	ENSP00000449317.1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16293 AN: 151458 Hom.: 1311 Cov.: 30

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0148

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0678

Gnomad OTH AF: 0.101

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

GnomAD4 genome AF: 0.108 AC: 16323 AN: 151578 Hom.: 1319 Cov.: 30 AF XY: 0.104 AC XY: 7719 AN XY: 74058

African (AFR) AF: 0.222 AC: 9152 AN: 41248

American (AMR) AF: 0.0827 AC: 1259 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0150 AC: 72 AN: 4802

European-Finnish (FIN) AF: 0.0466 AC: 488 AN: 10468

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.0677 AC: 4600 AN: 67914

Other (OTH) AF: 0.100 AC: 210 AN: 2092

Alfa AF: 0.0924 Hom.: 129

Bravo AF: 0.117

Asia WGS AF: 0.0290 AC: 104 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.34
DANN	Benign	0.54
PhyloP100		-1.1
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: rs4251487; hg19: chr12-44169882; COSMIC: COSV71210372; COSMIC: COSV71210372;