12-43768124-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016123.4(IRAK4):c.13A>G(p.Ile5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: IRAK4 NM_016123.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.207

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036036968).
• BP6: Variant 12-43768124-A-G is Benign according to our data. Variant chr12-43768124-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 763737.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK4	NM_016123.4	c.13A>G	p.Ile5Val	missense_variant	2/12	ENST00000613694.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK4	ENST00000613694.5	c.13A>G	p.Ile5Val	missense_variant	2/12	1	NM_016123.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000319 AC: 80 AN: 250822 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00435

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461268 Hom.: 0 Cov.: 30 AF XY: 0.0000688 AC XY: 50 AN XY: 726892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00225

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000305 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 67 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	1.8
Dann	Benign	0.28
DEOGEN2	Benign	0.0057	T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.70	T;.;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.14	N;.;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.10, 0.17
MVP		0.45
MPC		0.029
ClinPred		0.015	T
GERP RS		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56312115; hg19: chr12-44161927;