12-66189304-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_007199.3(IRAK3):ā€‹c.5C>Gā€‹(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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). 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: š‘“ 0.000046 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000029 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.632
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3333941).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRAK3NM_007199.3 linkuse as main transcriptc.5C>G p.Ala2Gly missense_variant 1/12 ENST00000261233.9
IRAK3NM_001142523.2 linkuse as main transcriptc.5C>G p.Ala2Gly missense_variant 1/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRAK3ENST00000261233.9 linkuse as main transcriptc.5C>G p.Ala2Gly missense_variant 1/121 NM_007199.3 P1Q9Y616-1
IRAK3ENST00000545837.1 linkuse as main transcriptc.5C>G p.Ala2Gly missense_variant 1/21
IRAK3ENST00000457197.2 linkuse as main transcriptc.5C>G p.Ala2Gly missense_variant 1/112 Q9Y616-2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.0000692
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152310
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000457
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000680

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 submitterclinical testingAmbry GeneticsJan 23, 2024The c.5C>G (p.A2G) alteration is located in exon 1 (coding exon 1) of the IRAK3 gene. This alteration results from a C to G substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a glycine (G). 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
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;T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.33
T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
0.46
N;.;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-1.7
N;D;N
REVEL
Benign
0.14
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.97
D;D;D
Vest4
0.092
MutPred
0.31
Gain of catalytic residue at G3 (P = 0);Gain of catalytic residue at G3 (P = 0);Gain of catalytic residue at G3 (P = 0);
MVP
0.83
MPC
0.022
ClinPred
0.58
D
GERP RS
2.7
Varity_R
0.31
gMVP
0.22

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs898461145; hg19: chr12-66583084; API