rs4251520

Variant names:

• chr12-43781535-T-C
• rs4251520
• NM_016123.4:c.942-772T>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.942-772T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,248 control chromosomes in the GnomAD database, including 1,424 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 0.13 (1424 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• Publications: 17 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	NM_016123.4	MANE Select	c.942-772T>C		intron	N/A	NP_057207.2	Q9NWZ3-1
	IRAK4	NM_001114182.3		c.942-772T>C		intron	N/A	NP_001107654.1	Q9NWZ3-1
	IRAK4	NM_001351345.2		c.942-772T>C		intron	N/A	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.942-772T>C		intron	N/A	ENSP00000479889.3	Q9NWZ3-1
	IRAK4	ENST00000551736.5	TSL:1	c.942-772T>C		intron	N/A	ENSP00000446490.1	Q9NWZ3-1
	IRAK4	ENST00000547101.5	TSL:1	n.*844-772T>C		intron	N/A	ENSP00000449317.1	F8VW24

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19644 AN: 152130 Hom.: 1423 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0852

Gnomad ASJ AF: 0.0863

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0904

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.113

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

GnomAD4 genome AF: 0.129 AC: 19651 AN: 152248 Hom.: 1424 Cov.: 32 AF XY: 0.128 AC XY: 9539 AN XY: 74438

African (AFR) AF: 0.188 AC: 7812 AN: 41520

American (AMR) AF: 0.0850 AC: 1300 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0863 AC: 299 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.0905 AC: 437 AN: 4828

European-Finnish (FIN) AF: 0.140 AC: 1487 AN: 10610

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7936 AN: 68018

Other (OTH) AF: 0.112 AC: 237 AN: 2114

Alfa AF: 0.118 Hom.: 1921

Bravo AF: 0.127

Asia WGS AF: 0.0340 AC: 121 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.55
PhyloP100		-0.31
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: rs4251520; hg19: chr12-44175338;