chr12-66224858-T-C

Variant names:

• chr12-66224858-T-C
• rs1370128
• NM_007199.3:c.654-1865T>C

Variant summary

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

The NM_007199.3(IRAK3):​c.654-1865T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 151,942 control chromosomes in the GnomAD database, including 24,878 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 0.55 (24878 hom., cov: 31)
• Consequence: IRAK3 NM_007199.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.782
• Publications: 13 publications found

Genes affected

IRAK3 (HGNC:17020): (interleukin 1 receptor associated kinase 3) This gene encodes a member of the interleukin-1 receptor-associated kinase protein family. Members of this family are essential components of the Toll/IL-R immune signal transduction pathways. This protein is primarily expressed in monocytes and macrophages and functions as a negative regulator of Toll-like receptor signaling. Mutations in this gene are associated with a susceptibility to asthma. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

IRAK3 Gene-Disease associations (from GenCC):

• asthma-related traits, susceptibility to, 5

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007199.3. 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
	IRAK3	NM_007199.3	MANE Select	c.654-1865T>C		intron	N/A	NP_009130.2
	IRAK3	NM_001142523.2		c.471-1865T>C		intron	N/A	NP_001135995.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK3	ENST00000261233.9	TSL:1 MANE Select	c.654-1865T>C		intron	N/A	ENSP00000261233.4
	IRAK3	ENST00000854785.1		c.651-1865T>C		intron	N/A	ENSP00000524844.1
	IRAK3	ENST00000947373.1		c.600-1865T>C		intron	N/A	ENSP00000617432.1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83546 AN: 151824 Hom.: 24868 Cov.: 31

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.550 AC: 83580 AN: 151942 Hom.: 24878 Cov.: 31 AF XY: 0.554 AC XY: 41138 AN XY: 74258

African (AFR) AF: 0.313 AC: 12969 AN: 41442

American (AMR) AF: 0.642 AC: 9791 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2218 AN: 3472

East Asian (EAS) AF: 0.469 AC: 2412 AN: 5148

South Asian (SAS) AF: 0.656 AC: 3164 AN: 4822

European-Finnish (FIN) AF: 0.698 AC: 7372 AN: 10556

Middle Eastern (MID) AF: 0.531 AC: 155 AN: 292

European-Non Finnish (NFE) AF: 0.648 AC: 43995 AN: 67942

Other (OTH) AF: 0.553 AC: 1165 AN: 2106

Alfa AF: 0.601 Hom.: 7427

Bravo AF: 0.535

Asia WGS AF: 0.558 AC: 1942 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.4
DANN	Benign	0.81
PhyloP100		0.78
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: rs1370128; hg19: chr12-66618638;