rs4251569

Positions:

• chr12-43761670-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016123.4(IRAK4):​c.-10+2654C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 152,186 control chromosomes in the GnomAD database, including 972 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 0.10 (972 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.719

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK4	NM_016123.4	c.-10+2654C>T		intron_variant		ENST00000613694.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK4	ENST00000613694.5	c.-10+2654C>T		intron_variant		1	NM_016123.4	P1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15387 AN: 152068 Hom.: 969 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0852

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.126

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

GnomAD4 genome AF: 0.101 AC: 15393 AN: 152186 Hom.: 972 Cov.: 32 AF XY: 0.100 AC XY: 7474 AN XY: 74408

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.0852

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.129

Alfa AF: 0.109 Hom.: 177

Bravo AF: 0.100

Asia WGS AF: 0.140 AC: 490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs4251569; hg19: chr12-44155473;