rs10506481

Variant names:

• chr12-66250331-T-C
• rs10506481
• NM_007199.3:c.*2160T>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.*2160T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0897 in 152,256 control chromosomes in the GnomAD database, including 658 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 0.090 (658 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: IRAK3 NM_007199.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 9 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.105 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK3	NM_007199.3	MANE Select	c.*2160T>C		3_prime_UTR	Exon 12 of 12	NP_009130.2	Q9Y616-1
	IRAK3	NM_001142523.2		c.*2160T>C		3_prime_UTR	Exon 11 of 11	NP_001135995.1	Q9Y616-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK3	ENST00000261233.9	TSL:1 MANE Select	c.*2160T>C		3_prime_UTR	Exon 12 of 12	ENSP00000261233.4	Q9Y616-1

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13645 AN: 152136 Hom.: 655 Cov.: 32

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.0954

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0883

Gnomad OTH AF: 0.0827

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0897 AC: 13660 AN: 152254 Hom.: 658 Cov.: 32 AF XY: 0.0888 AC XY: 6610 AN XY: 74454

African (AFR) AF: 0.0907 AC: 3769 AN: 41538

American (AMR) AF: 0.0954 AC: 1459 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 464 AN: 3470

East Asian (EAS) AF: 0.0262 AC: 136 AN: 5190

South Asian (SAS) AF: 0.113 AC: 546 AN: 4822

European-Finnish (FIN) AF: 0.0843 AC: 894 AN: 10608

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0883 AC: 6004 AN: 68010

Other (OTH) AF: 0.0847 AC: 179 AN: 2114

Alfa AF: 0.0864 Hom.: 1124

Bravo AF: 0.0911

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.31
DANN	Benign	0.43
PhyloP100		-1.7
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: rs10506481; hg19: chr12-66644111;