12-43768149-G-T

Variant names:

• chr12-43768149-G-T
• rs1163230363
• NM_016123.4:c.38G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016123.4(IRAK4):​c.38G>T​(p.Cys13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IRAK4 NM_016123.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.894

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17491004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.38G>T	p.Cys13Phe	missense_variant	Exon 2 of 12	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.38G>T	p.Cys13Phe	missense_variant	Exon 2 of 12	1	NM_016123.4	ENSP00000479889.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250936 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461412 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.039	T;T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;L;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;.;N;N
REVEL	Benign	0.048
Sift	Benign	0.040	D;.;T;T
Sift4G	Uncertain	0.057	T;D;D;T
Polyphen		0.0090	.;B;B;.
Vest4		0.44, 0.46
MutPred		0.44		Gain of catalytic residue at N15 (P = 0.0016);Gain of catalytic residue at N15 (P = 0.0016);Gain of catalytic residue at N15 (P = 0.0016);Gain of catalytic residue at N15 (P = 0.0016);
MVP		0.74
MPC		0.046
ClinPred		0.16	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.50

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: rs1163230363; hg19: chr12-44161952; COSMIC: COSV71211065;