12-43784280-C-T

Variant names:

• chr12-43784280-C-T
• rs4251532
• NM_016123.4:c.1188+556C>T

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.1188+556C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,044 control chromosomes in the GnomAD database, including 6,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (6512 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.627
• Publications: 7 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=-1.01).
• BP6: Variant 12-43784280-C-T is Benign according to our data. Variant chr12-43784280-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266473.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.1188+556C>T		intron_variant	Intron 10 of 11	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.1188+556C>T		intron_variant	Intron 10 of 11	1	NM_016123.4	ENSP00000479889.3

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35147 AN: 151926 Hom.: 6484 Cov.: 32

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0933

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.232 AC: 35212 AN: 152044 Hom.: 6512 Cov.: 32 AF XY: 0.227 AC XY: 16894 AN XY: 74322

African (AFR) AF: 0.517 AC: 21402 AN: 41426

American (AMR) AF: 0.175 AC: 2675 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3468

East Asian (EAS) AF: 0.161 AC: 831 AN: 5162

South Asian (SAS) AF: 0.141 AC: 677 AN: 4816

European-Finnish (FIN) AF: 0.0933 AC: 987 AN: 10582

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7384 AN: 67986

Other (OTH) AF: 0.220 AC: 465 AN: 2114

Alfa AF: 0.112 Hom.: 354

Bravo AF: 0.249

Asia WGS AF: 0.185 AC: 644 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.41
PhyloP100		-0.63
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: rs4251532; hg19: chr12-44178083;