12-43772190-C-G

Position:

• chr12-43772190-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016123.4(IRAK4):​c.318C>G​(p.Pro106=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00631 in 1,612,940 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (44 hom.)
• Consequence: IRAK4 NM_016123.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.646

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-43772190-C-G is Benign according to our data. Variant chr12-43772190-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 308725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-43772190-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.646 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.318C>G	p.Pro106=	synonymous_variant	4/12	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.318C>G	p.Pro106=	synonymous_variant	4/12	1	NM_016123.4	ENSP00000479889	P1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 777 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00566 AC: 1417 AN: 250398 Hom.: 6 AF XY: 0.00574 AC XY: 777 AN XY: 135422

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.00805

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00644 AC: 9407 AN: 1460668 Hom.: 44 Cov.: 31 AF XY: 0.00636 AC XY: 4622 AN XY: 726700

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.00721

Gnomad4 OTH exome AF: 0.00593

GnomAD4 genome AF: 0.00510 AC: 777 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00497 AC XY: 370 AN XY: 74450

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.00753

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00627 Hom.: 3

Bravo AF: 0.00457

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 67 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	IRAK4: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.6
DANN	Benign	0.82

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: rs56338336; hg19: chr12-44165993; COSMIC: COSV101471785; COSMIC: COSV101471785;