chr12-66189396-G-C

Variant names:

• chr12-66189396-G-C
• rs1161892905
• NM_007199.3:c.97G>C

Variant summary

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

The NM_007199.3(IRAK3):​c.97G>C​(p.Asp33His) variant causes a missense change. The variant allele was found at a frequency of 0.00000152 in 1,312,598 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. D33N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: IRAK3 NM_007199.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• 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.97G>C	p.Asp33His	missense_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.97G>C	p.Asp33His	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.97G>C	p.Asp33His	missense_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000545837.1	c.97G>C	p.Asp33His	missense_variant	Exon 1 of 2	1		ENSP00000441321.1
IRAK3	ENST00000457197.2	c.97G>C	p.Asp33His	missense_variant	Exon 1 of 11	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1312598 Hom.: 0 Cov.: 31 AF XY: 0.00000311 AC XY: 2 AN XY: 642876

African (AFR) AF: 0.00 AC: 0 AN: 26516

American (AMR) AF: 0.00 AC: 0 AN: 28772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23010

East Asian (EAS) AF: 0.00 AC: 0 AN: 29490

South Asian (SAS) AF: 0.00 AC: 0 AN: 73302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3870

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1040768

Other (OTH) AF: 0.00 AC: 0 AN: 54308

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	D;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.4	M;.;M
PhyloP100		4.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;D;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.36
MutPred		0.69		Gain of catalytic residue at D36 (P = 0);Gain of catalytic residue at D36 (P = 0);Gain of catalytic residue at D36 (P = 0);
MVP		0.93
MPC		0.18
ClinPred		0.99	D
GERP RS		3.4
PromoterAI		-0.081	Neutral
Varity_R		0.80
gMVP		0.60
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1161892905; hg19: chr12-66583176;