chr12-43770638-C-T

Variant names:

• chr12-43770638-C-T
• rs4251466
• NM_016123.4:c.162-582C>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.162-582C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,164 control chromosomes in the GnomAD database, including 1,350 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 0.12 (1350 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.478
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 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.162-582C>T		intron	N/A	NP_057207.2
	IRAK4	NM_001114182.3		c.162-582C>T		intron	N/A	NP_001107654.1
	IRAK4	NM_001351345.2		c.162-582C>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.162-582C>T		intron	N/A	ENSP00000479889.3
	IRAK4	ENST00000551736.5	TSL:1	c.162-582C>T		intron	N/A	ENSP00000446490.1
	IRAK4	ENST00000547101.5	TSL:1	n.162-400C>T		intron	N/A	ENSP00000449317.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18820 AN: 152046 Hom.: 1344 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.124 AC: 18846 AN: 152164 Hom.: 1350 Cov.: 32 AF XY: 0.122 AC XY: 9065 AN XY: 74396

African (AFR) AF: 0.193 AC: 7991 AN: 41478

American (AMR) AF: 0.127 AC: 1949 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 536 AN: 3468

East Asian (EAS) AF: 0.105 AC: 542 AN: 5178

South Asian (SAS) AF: 0.117 AC: 562 AN: 4814

European-Finnish (FIN) AF: 0.0607 AC: 643 AN: 10594

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6245 AN: 68018

Other (OTH) AF: 0.135 AC: 285 AN: 2112

Alfa AF: 0.108 Hom.: 1211

Bravo AF: 0.131

Asia WGS AF: 0.122 AC: 423 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.4
DANN	Benign	0.46
PhyloP100		-0.48
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: rs4251466; hg19: chr12-44164441;