rs1555167566

Variant names:

• chr12-43771278-TG-T
• rs1555167566
• NM_016123.4:c.224delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016123.4(IRAK4):​c.224delG​(p.Gly75AlafsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRAK4 NM_016123.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.01
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-43771278-TG-T is Pathogenic according to our data. Variant chr12-43771278-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 464933.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	NM_016123.4	MANE Select	c.224delG	p.Gly75AlafsTer14	frameshift	Exon 3 of 12	NP_057207.2	Q9NWZ3-1
	IRAK4	NM_001114182.3		c.224delG	p.Gly75AlafsTer14	frameshift	Exon 4 of 13	NP_001107654.1	Q9NWZ3-1
	IRAK4	NM_001351345.2		c.224delG	p.Gly75AlafsTer14	frameshift	Exon 4 of 13	NP_001338274.1	Q69FE3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.224delG	p.Gly75AlafsTer14	frameshift	Exon 3 of 12	ENSP00000479889.3	Q9NWZ3-1
	IRAK4	ENST00000551736.5	TSL:1	c.224delG	p.Gly75AlafsTer14	frameshift	Exon 4 of 13	ENSP00000446490.1	Q9NWZ3-1
	IRAK4	ENST00000547101.5	TSL:1	n.*126delG		non_coding_transcript_exon	Exon 4 of 13	ENSP00000449317.1	F8VW24

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Immunodeficiency 67 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1555167566; hg19: chr12-44165081;