12-43770886-G-A

Variant names:

• chr12-43770886-G-A
• rs1461567
• NM_016123.4:c.162-334G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016123.4(IRAK4):​c.162-334G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,058 control chromosomes in the GnomAD database, including 4,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (4916 hom., cov: 31)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.578
• Publications: 29 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 12-43770886-G-A is Benign according to our data. Variant chr12-43770886-G-A is described in ClinVar as Benign. ClinVar VariationId is 2628208.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	NM_016123.4	MANE Select	c.162-334G>A		intron	N/A	NP_057207.2
	IRAK4	NM_001114182.3		c.162-334G>A		intron	N/A	NP_001107654.1
	IRAK4	NM_001351345.2		c.162-334G>A		intron	N/A	NP_001338274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.162-334G>A		intron	N/A	ENSP00000479889.3
	IRAK4	ENST00000551736.5	TSL:1	c.162-334G>A		intron	N/A	ENSP00000446490.1
	IRAK4	ENST00000547101.5	TSL:1	n.162-152G>A		intron	N/A	ENSP00000449317.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34302 AN: 151940 Hom.: 4913 Cov.: 31

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.234

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.226 AC: 34307 AN: 152058 Hom.: 4916 Cov.: 31 AF XY: 0.234 AC XY: 17397 AN XY: 74326

African (AFR) AF: 0.0489 AC: 2030 AN: 41502

American (AMR) AF: 0.263 AC: 4023 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1022 AN: 3472

East Asian (EAS) AF: 0.468 AC: 2416 AN: 5158

South Asian (SAS) AF: 0.382 AC: 1843 AN: 4824

European-Finnish (FIN) AF: 0.323 AC: 3410 AN: 10558

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.277 AC: 18812 AN: 67948

Other (OTH) AF: 0.237 AC: 501 AN: 2114

Alfa AF: 0.261 Hom.: 14218

Bravo AF: 0.210

Asia WGS AF: 0.421 AC: 1460 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied by a panel of primary immunodeficiencies. Number of patients: 38. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.9
DANN	Benign	0.43
PhyloP100		-0.58
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: rs1461567; hg19: chr12-44164689; COSMIC: COSV107527364; COSMIC: COSV107527364;