rs56338336

Variant names:

• chr12-43772190-C-G
• rs56338336
• NM_016123.4:c.318C>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016123.4(IRAK4):​c.318C>G​(p.Pro106Pro) 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
• Publications: 3 publications found

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]

IRAK4 Gene-Disease associations (from GenCC):

• immunodeficiency 67

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 308725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.646 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	NM_016123.4	MANE Select	c.318C>G	p.Pro106Pro	synonymous	Exon 4 of 12	NP_057207.2	Q9NWZ3-1
	IRAK4	NM_001114182.3		c.318C>G	p.Pro106Pro	synonymous	Exon 5 of 13	NP_001107654.1	Q9NWZ3-1
	IRAK4	NM_001351345.2		c.318C>G	p.Pro106Pro	synonymous	Exon 5 of 13	NP_001338274.1	Q69FE3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.318C>G	p.Pro106Pro	synonymous	Exon 4 of 12	ENSP00000479889.3	Q9NWZ3-1
	IRAK4	ENST00000551736.5	TSL:1	c.318C>G	p.Pro106Pro	synonymous	Exon 5 of 13	ENSP00000446490.1	Q9NWZ3-1
	IRAK4	ENST00000547101.5	TSL:1	n.*220C>G		non_coding_transcript_exon	Exon 5 of 13	ENSP00000449317.1	F8VW24

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

GnomAD2 exomes AF: 0.00566 AC: 1417 AN: 250398 AF XY: 0.00574

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 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

African (AFR) AF: 0.000418 AC: 14 AN: 33468

American (AMR) AF: 0.00335 AC: 150 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00205 AC: 177 AN: 86238

European-Finnish (FIN) AF: 0.0122 AC: 644 AN: 52800

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00721 AC: 8019 AN: 1111498

Other (OTH) AF: 0.00593 AC: 358 AN: 60374

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

African (AFR) AF: 0.00113 AC: 47 AN: 41560

American (AMR) AF: 0.00490 AC: 75 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00753 AC: 512 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 67 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.6
DANN	Benign	0.82
PhyloP100		0.65
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

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