12-43760604-G-C

Variant names:

• chr12-43760604-G-C
• rs4251429
• NM_016123.4:c.-10+1588G>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.-10+1588G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 152,190 control chromosomes in the GnomAD database, including 1,852 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 0.099 (1852 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.560
• Publications: 6 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 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.-10+1588G>C		intron	N/A	NP_057207.2
	IRAK4	NM_001114182.3		c.-57-321G>C		intron	N/A	NP_001107654.1
	IRAK4	NM_001351345.2		c.-57-321G>C		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.-10+1588G>C		intron	N/A	ENSP00000479889.3
	IRAK4	ENST00000551736.5	TSL:1	c.-57-321G>C		intron	N/A	ENSP00000446490.1
	IRAK4	ENST00000547101.5	TSL:1	n.-10+1588G>C		intron	N/A	ENSP00000449317.1

Frequencies

GnomAD3 genomes AF: 0.0985 AC: 14980 AN: 152072 Hom.: 1848 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.0562

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0804

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

GnomAD4 genome AF: 0.0986 AC: 15012 AN: 152190 Hom.: 1852 Cov.: 32 AF XY: 0.0969 AC XY: 7209 AN XY: 74406

African (AFR) AF: 0.292 AC: 12120 AN: 41470

American (AMR) AF: 0.0407 AC: 622 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.0567 AC: 294 AN: 5186

South Asian (SAS) AF: 0.0238 AC: 115 AN: 4826

European-Finnish (FIN) AF: 0.0345 AC: 366 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0171 AC: 1164 AN: 68024

Other (OTH) AF: 0.0795 AC: 168 AN: 2112

Alfa AF: 0.0107 Hom.: 8

Bravo AF: 0.108

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.27
DANN	Benign	0.43
PhyloP100		-0.56
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: rs4251429; hg19: chr12-44154407;