12-66189408-G-A

Variant names:

• chr12-66189408-G-A
• rs1456709729
• NM_007199.3:c.109G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007199.3(IRAK3):​c.109G>A​(p.Gly37Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,808 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G37R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: IRAK3 NM_007199.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.109G>A	p.Gly37Ser	missense_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.109G>A	p.Gly37Ser	missense_variant	Exon 1 of 11		NP_001135995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9	c.109G>A	p.Gly37Ser	missense_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000545837.1	c.109G>A	p.Gly37Ser	missense_variant	Exon 1 of 2	1		ENSP00000441321.1
IRAK3	ENST00000457197.2	c.109G>A	p.Gly37Ser	missense_variant	Exon 1 of 11	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151732 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.0000160 AC: 1 AN: 62438 AF XY: 0.0000277

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.79e-7 AC: 1 AN: 1283076 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 626644

African (AFR) AF: 0.00 AC: 0 AN: 25790

American (AMR) AF: 0.00 AC: 0 AN: 24694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21766

East Asian (EAS) AF: 0.00 AC: 0 AN: 28238

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1025228

Other (OTH) AF: 0.00 AC: 0 AN: 52880

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151732 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74086

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.85	D;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.67	N;.;N
PhyloP100		3.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.53	N;D;N
REVEL	Uncertain	0.40
Sift	Benign	0.41	T;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.18
MutPred		0.47		Gain of catalytic residue at L39 (P = 0);Gain of catalytic residue at L39 (P = 0);Gain of catalytic residue at L39 (P = 0);
MVP		0.96
MPC		0.094
ClinPred		0.81	D
GERP RS		3.4
PromoterAI		0.020	Neutral
Varity_R		0.090
gMVP		0.37
Mutation Taster		=66/34	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: rs1456709729; hg19: chr12-66583188;