rs1141168

Positions:

• chr12-43788903-A-G
• chr12-43788903-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016123.4(IRAK4):​c.*2188A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 151,854 control chromosomes in the GnomAD database, including 14,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14413 hom., cov: 30)
  • Exomes 𝑓: 0.45 (3 hom.)
• Consequence: IRAK4 NM_016123.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.301

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-43788903-A-G is Benign according to our data. Variant chr12-43788903-A-G is described in ClinVar as [Benign]. Clinvar id is 308762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.*2188A>G		3_prime_UTR_variant	12/12	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.*2188A>G		3_prime_UTR_variant	12/12	1	NM_016123.4	ENSP00000479889	P1
IRAK4	ENST00000696791.1	c.*3473A>G		3_prime_UTR_variant, NMD_transcript_variant	13/13			ENSP00000512873
IRAK4	ENST00000696792.1	c.*2316A>G		3_prime_UTR_variant, NMD_transcript_variant	5/5			ENSP00000512874
IRAK4	ENST00000696795.1	c.*1018+2346A>G		intron_variant, NMD_transcript_variant				ENSP00000512876

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65100 AN: 151714 Hom.: 14413 Cov.: 30

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.428

GnomAD4 exome AF: 0.455 AC: 10 AN: 22 Hom.: 3 Cov.: 0 AF XY: 0.583 AC XY: 7 AN XY: 12

Gnomad4 NFE exome AF: 0.455

GnomAD4 genome AF: 0.429 AC: 65108 AN: 151832 Hom.: 14413 Cov.: 30 AF XY: 0.434 AC XY: 32166 AN XY: 74198

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.513

Gnomad4 SAS AF: 0.517

Gnomad4 FIN AF: 0.511

Gnomad4 NFE AF: 0.477

Gnomad4 OTH AF: 0.429

Alfa AF: 0.465 Hom.: 16501

Bravo AF: 0.414

Asia WGS AF: 0.509 AC: 1769 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 67 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

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	-0.85
CADD	Benign	3.4
DANN	Benign	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: rs1141168; hg19: chr12-44182706;