12-66189304-C-G

Variant names:

• chr12-66189304-C-G
• rs898461145
• NM_007199.3:c.5C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_007199.3(IRAK3):​c.5C>G​(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000716 in 1,536,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: IRAK3 NM_007199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.632
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3333941).
• BS2: High AC in GnomAd4 at 7 AD gene.

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.5C>G	p.Ala2Gly	missense	Exon 1 of 12	NP_009130.2	Q9Y616-1
	IRAK3	NM_001142523.2		c.5C>G	p.Ala2Gly	missense	Exon 1 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.5C>G	p.Ala2Gly	missense	Exon 1 of 12	ENSP00000261233.4	Q9Y616-1
	IRAK3	ENST00000545837.1	TSL:1	c.5C>G	p.Ala2Gly	missense	Exon 1 of 2	ENSP00000441321.1	F5GYN6
	IRAK3	ENST00000854785.1		c.5C>G	p.Ala2Gly	missense	Exon 1 of 12	ENSP00000524844.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1383824 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 683098

African (AFR) AF: 0.00 AC: 0 AN: 31690

American (AMR) AF: 0.00 AC: 0 AN: 35900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25072

East Asian (EAS) AF: 0.00 AC: 0 AN: 36028

South Asian (SAS) AF: 0.00 AC: 0 AN: 79386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079644

Other (OTH) AF: 0.0000692 AC: 4 AN: 57766

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.63
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.092
MutPred		0.31		Gain of catalytic residue at G3 (P = 0)
MVP		0.83
MPC		0.022
ClinPred		0.58	D
GERP RS		2.7
PromoterAI		-0.31	Neutral
Varity_R		0.31
gMVP		0.22
Mutation Taster		=87/13	polymorphism

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: rs898461145; hg19: chr12-66583084;