12-43768143-T-G

Position:

• chr12-43768143-T-G

Variant summary

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

The ENST00000613694.5(IRAK4):​c.32T>G​(p.Val11Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRAK4 ENST00000613694.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.32T>G	p.Val11Gly	missense_variant	2/12	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.32T>G	p.Val11Gly	missense_variant	2/12	1	NM_016123.4	ENSP00000479889	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 67 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 01, 2023

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 11 of the IRAK4 protein (p.Val11Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IRAK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 960941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IRAK4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.2	.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.9	D;.;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.93	.;P;P;.
Vest4		0.50, 0.67
MutPred		0.44		Gain of catalytic residue at Y10 (P = 2e-04);Gain of catalytic residue at Y10 (P = 2e-04);Gain of catalytic residue at Y10 (P = 2e-04);Gain of catalytic residue at Y10 (P = 2e-04);
MVP		0.92
MPC		0.22
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.83

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: rs1940363408; hg19: chr12-44161946;