chr12-43768965-A-C

Variant names:

• chr12-43768965-A-C
• rs4251460
• NM_016123.4:c.161+693A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016123.4(IRAK4):​c.161+693A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,154 control chromosomes in the GnomAD database, including 6,493 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (6493 hom., cov: 32)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK4	NM_016123.4	c.161+693A>C		intron_variant	Intron 2 of 11	ENST00000613694.5	NP_057207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK4	ENST00000613694.5	c.161+693A>C		intron_variant	Intron 2 of 11	1	NM_016123.4	ENSP00000479889.3

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35155 AN: 152036 Hom.: 6465 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0953

Gnomad MID AF: 0.204

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: 0.231 AC: 35220 AN: 152154 Hom.: 6493 Cov.: 32 AF XY: 0.227 AC XY: 16910 AN XY: 74390

African (AFR) AF: 0.515 AC: 21369 AN: 41462

American (AMR) AF: 0.175 AC: 2673 AN: 15292

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

East Asian (EAS) AF: 0.161 AC: 831 AN: 5176

South Asian (SAS) AF: 0.141 AC: 683 AN: 4832

European-Finnish (FIN) AF: 0.0953 AC: 1011 AN: 10604

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.109 AC: 7397 AN: 68002

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

Alfa AF: 0.117 Hom.: 465

Bravo AF: 0.249

Asia WGS AF: 0.184 AC: 639 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.36
PhyloP100		-0.82
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: rs4251460; hg19: chr12-44162768;