rs121908002

Variant names:

• chr12-43778238-C-T
• rs121908002
• NM_016123.4:c.877C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_016123.4(IRAK4):​c.877C>T​(p.Gln293*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,611,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: IRAK4 NM_016123.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.62
• Publications: 42 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-43778238-C-T is Pathogenic according to our data. Variant chr12-43778238-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.877C>T	p.Gln293*	stop_gained	Exon 8 of 12	NP_057207.2	Q9NWZ3-1
	IRAK4	NM_001114182.3		c.877C>T	p.Gln293*	stop_gained	Exon 9 of 13	NP_001107654.1	Q9NWZ3-1
	IRAK4	NM_001351345.2		c.877C>T	p.Gln293*	stop_gained	Exon 9 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.877C>T	p.Gln293*	stop_gained	Exon 8 of 12	ENSP00000479889.3	Q9NWZ3-1
	IRAK4	ENST00000551736.5	TSL:1	c.877C>T	p.Gln293*	stop_gained	Exon 9 of 13	ENSP00000446490.1	Q9NWZ3-1
	IRAK4	ENST00000547101.5	TSL:1	n.*779C>T		non_coding_transcript_exon	Exon 9 of 13	ENSP00000449317.1	F8VW24

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251346 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000676 AC: 987 AN: 1459592 Hom.: 0 Cov.: 28 AF XY: 0.000666 AC XY: 484 AN XY: 726320

African (AFR) AF: 0.0000598 AC: 2 AN: 33434

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000872 AC: 968 AN: 1110020

Other (OTH) AF: 0.000232 AC: 14 AN: 60326

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74288

African (AFR) AF: 0.0000966 AC: 4 AN: 41414

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68010

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Immunodeficiency 67 (5)
4	-	-	not provided (4)
1	-	-	IRAK4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		2.6
Vest4		0.90
GERP RS		5.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs121908002; hg19: chr12-44172041;