12-66203860-C-T

Variant summary

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

The NM_007199.3(IRAK3):​c.283C>T​(p.His95Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H95R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 missense

Scores

1
13
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16
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.283C>T p.His95Tyr missense_variant 2/12 ENST00000261233.9
IRAK3NM_001142523.2 linkuse as main transcriptc.134-5596C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRAK3ENST00000261233.9 linkuse as main transcriptc.283C>T p.His95Tyr missense_variant 2/121 NM_007199.3 P1Q9Y616-1
IRAK3ENST00000457197.2 linkuse as main transcriptc.134-5596C>T intron_variant 2 Q9Y616-2

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251232
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135786
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461588
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
727106
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:
0.0000207
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000724
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2

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 02, 2023The c.283C>T (p.H95Y) alteration is located in exon 2 (coding exon 2) of the IRAK3 gene. This alteration results from a C to T substitution at nucleotide position 283, causing the histidine (H) at amino acid position 95 to be replaced by a tyrosine (Y). 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
Uncertain
0.48
BayesDel_addAF
Uncertain
0.057
T
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.076
D
MetaRNN
Uncertain
0.62
D
MetaSVM
Uncertain
0.37
D
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.71
N
REVEL
Uncertain
0.51
Sift
Uncertain
0.024
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.50
MVP
0.90
MPC
0.19
ClinPred
0.74
D
GERP RS
5.9
Varity_R
0.30
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs372148641; hg19: chr12-66597640; API