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GeneBe

12-66209521-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_Strong

The NM_007199.3(IRAK3):c.381+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,547,060 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

IRAK3
NM_007199.3 splice_donor

Scores

2
2
3
Splicing: ADA: 1.000
2

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 1.80
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 Pathogenic. Variant got 14 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.7, offset of 5, new splice context is: agaGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRAK3NM_007199.3 linkuse as main transcriptc.381+1G>T splice_donor_variant ENST00000261233.9
IRAK3NM_001142523.2 linkuse as main transcriptc.198+1G>T splice_donor_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRAK3ENST00000261233.9 linkuse as main transcriptc.381+1G>T splice_donor_variant 1 NM_007199.3 P1Q9Y616-1
IRAK3ENST00000457197.2 linkuse as main transcriptc.198+1G>T splice_donor_variant 2 Q9Y616-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000131
AC:
20
AN:
152134
Hom.:
0
Cov.:
32
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:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000120
AC:
30
AN:
250930
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135636
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.000220
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.000100
AC:
140
AN:
1394808
Hom.:
0
Cov.:
23
AF XY:
0.000100
AC XY:
70
AN XY:
698030
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000673
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.000110
Gnomad4 OTH exome
AF:
0.000224
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000131
AC:
20
AN:
152252
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000156
Hom.:
0
Bravo
AF:
0.0000982
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000988
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3476
EpiCase
AF:
0.000655
EpiControl
AF:
0.000415

ClinVar

Significance: risk factor
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Asthma-related traits, susceptibility to, 5 Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJun 01, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Benign
-0.24
Cadd
Uncertain
24
Dann
Benign
0.95
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.80
D
MutationTaster
Benign
1.0
D;D
GERP RS
4.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.97
Position offset: -1

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: rs150116809; hg19: chr12-66603301; API