12-66211448-A-G

Position:

• chr12-66211448-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_007199.3(IRAK3):​c.439A>G​(p.Ile147Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 1,589,414 control chromosomes in the GnomAD database, including 652,620 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.79 (50526 hom., cov: 32)
  • Exomes 𝑓: 0.91 (602094 hom.)
• Consequence: IRAK3 NM_007199.3 missense, splice_region
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.420

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8947065E-7).
• BP6: Variant 12-66211448-A-G is Benign according to our data. Variant chr12-66211448-A-G is described in ClinVar as [Benign]. Clinvar id is 3059815.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRAK3	NM_007199.3	c.439A>G	p.Ile147Val	missense_variant, splice_region_variant	5/12	ENST00000261233.9
IRAK3	NM_001142523.2	c.256A>G	p.Ile86Val	missense_variant, splice_region_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRAK3	ENST00000261233.9	c.439A>G	p.Ile147Val	missense_variant, splice_region_variant	5/12	1	NM_007199.3	P1
IRAK3	ENST00000457197.2	c.256A>G	p.Ile86Val	missense_variant, splice_region_variant	4/11	2

Frequencies

GnomAD3 genomes AF: 0.790 AC: 120057 AN: 152054 Hom.: 50509 Cov.: 32

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.897

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.869

Gnomad FIN AF: 0.914

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.827

GnomAD3 exomes AF: 0.872 AC: 218441 AN: 250616 Hom.: 97642 AF XY: 0.879 AC XY: 119179 AN XY: 135570

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.945

Gnomad ASJ exome AF: 0.935

Gnomad EAS exome AF: 0.597

Gnomad SAS exome AF: 0.890

Gnomad FIN exome AF: 0.911

Gnomad NFE exome AF: 0.931

Gnomad OTH exome AF: 0.896

GnomAD4 exome AF: 0.911 AC: 1308715 AN: 1437242 Hom.: 602094 Cov.: 29 AF XY: 0.911 AC XY: 652923 AN XY: 716676

Gnomad4 AFR exome AF: 0.467

Gnomad4 AMR exome AF: 0.938

Gnomad4 ASJ exome AF: 0.938

Gnomad4 EAS exome AF: 0.592

Gnomad4 SAS exome AF: 0.888

Gnomad4 FIN exome AF: 0.911

Gnomad4 NFE exome AF: 0.937

Gnomad4 OTH exome AF: 0.881

GnomAD4 genome AF: 0.789 AC: 120113 AN: 152172 Hom.: 50526 Cov.: 32 AF XY: 0.791 AC XY: 58830 AN XY: 74408

Gnomad4 AFR AF: 0.480

Gnomad4 AMR AF: 0.897

Gnomad4 ASJ AF: 0.937

Gnomad4 EAS AF: 0.600

Gnomad4 SAS AF: 0.869

Gnomad4 FIN AF: 0.914

Gnomad4 NFE AF: 0.933

Gnomad4 OTH AF: 0.828

Alfa AF: 0.904 Hom.: 151744

Bravo AF: 0.773

TwinsUK AF: 0.944 AC: 3502

ALSPAC AF: 0.937 AC: 3611

ESP6500AA AF: 0.493 AC: 2170

ESP6500EA AF: 0.933 AC: 8022

ExAC AF: 0.862 AC: 104622

Asia WGS AF: 0.726 AC: 2527 AN: 3478

EpiCase AF: 0.933

EpiControl AF: 0.926

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

IRAK3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.49
DANN	Benign	0.23
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	6.9e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.033
Sift	Benign	0.61	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0010	B;B
Vest4		0.027
MPC		0.021
ClinPred		0.0014	T
GERP RS		0.74
Varity_R		0.028
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1152888; hg19: chr12-66605228; COSMIC: COSV54160564;