12-66203730-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007199.3(IRAK3):ā€‹c.153C>Gā€‹(p.Ser51Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000089 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.173
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRAK3NM_007199.3 linkuse as main transcriptc.153C>G p.Ser51Arg missense_variant 2/12 ENST00000261233.9
IRAK3NM_001142523.2 linkuse as main transcriptc.134-5726C>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRAK3ENST00000261233.9 linkuse as main transcriptc.153C>G p.Ser51Arg missense_variant 2/121 NM_007199.3 P1Q9Y616-1
IRAK3ENST00000457197.2 linkuse as main transcriptc.134-5726C>G intron_variant 2 Q9Y616-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251188
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135758
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461732
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 GeneticsMay 26, 2022The c.153C>G (p.S51R) alteration is located in exon 2 (coding exon 2) of the IRAK3 gene. This alteration results from a C to G substitution at nucleotide position 153, causing the serine (S) at amino acid position 51 to be replaced by an arginine (R). 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
0.82
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.12
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.74
T
M_CAP
Uncertain
0.15
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
0.89
D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-2.1
N
REVEL
Uncertain
0.60
Sift
Uncertain
0.028
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.99
D
Vest4
0.59
MutPred
0.67
Gain of MoRF binding (P = 0.0199);
MVP
0.97
MPC
0.18
ClinPred
0.85
D
GERP RS
0.20
Varity_R
0.17
gMVP
0.52

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: rs764826050; hg19: chr12-66597510; API