Variant chr12-66189430-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_007199.3(IRAK3):c.131T>C(p.Leu44Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000238 in 1,300,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 missense, splice_region

Scores

Splicing: ADA: 0.004310

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRAK3	NM_007199.3 linkuse as main transcript	c.131T>C	p.Leu44Pro	missense_variant, splice_region_variant	1/12	ENST00000261233.9	NP_009130.2	Q9Y616-1
IRAK3	NM_001142523.2 linkuse as main transcript	c.131T>C	p.Leu44Pro	missense_variant, splice_region_variant	1/11		NP_001135995.1	Q9Y616-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IRAK3	ENST00000261233.9 linkuse as main transcript	c.131T>C	p.Leu44Pro	missense_variant, splice_region_variant	1/12	1	NM_007199.3	ENSP00000261233.4	Q9Y616-1
IRAK3	ENST00000545837.1 linkuse as main transcript	c.131T>C	p.Leu44Pro	missense_variant, splice_region_variant	1/2	1		ENSP00000441321.1	F5GYN6
IRAK3	ENST00000457197.2 linkuse as main transcript	c.131T>C	p.Leu44Pro	missense_variant, splice_region_variant	1/11	2		ENSP00000409852.2	Q9Y616-2

Frequencies

GnomAD3 genomes

AF:

0.0000595

AC:

AN:

151318

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1149636

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

554696

show subpopulations

Gnomad4 AFR exome

AF:

0.0000856

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000209

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000595

AC:

AN:

151318

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73880

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The c.131T>C (p.L44P) alteration is located in exon 1 (coding exon 1) of the IRAK3 gene. This alteration results from a T to C substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

D;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.62

T;T;T

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

-0.028

MutationAssessor

Uncertain

2.4

M;.;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.9

D;D;N

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.72

MutPred

0.82

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

0.91

MPC

0.20

ClinPred

0.94

GERP RS

3.4

Varity_R

0.81

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0043

dbscSNV1_RF

Benign

0.11

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over