rs1141168

Variant names:

• chr12-43788903-A-G
• rs1141168
• NM_016123.4:c.*2188A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.*2188A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.*2188A>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_016123.4	ENSP00000479889.3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.455 AC: 10 AN: 22

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.303 AC: 12535 AN: 41392

American (AMR) AF: 0.421 AC: 6425 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1887 AN: 3466

East Asian (EAS) AF: 0.513 AC: 2638 AN: 5144

South Asian (SAS) AF: 0.517 AC: 2495 AN: 4822

European-Finnish (FIN) AF: 0.511 AC: 5373 AN: 10518

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32369 AN: 67912

Other (OTH) AF: 0.429 AC: 907 AN: 2114

Alfa AF: 0.462 Hom.: 41791

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.4
DANN	Benign	0.83
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs1141168; hg19: chr12-44182706;