rs114951157
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016123.4(IRAK4):c.547C>T(p.Arg183Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,610,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_016123.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IRAK4 | NM_016123.4 | c.547C>T | p.Arg183Ter | stop_gained | 5/12 | ENST00000613694.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IRAK4 | ENST00000613694.5 | c.547C>T | p.Arg183Ter | stop_gained | 5/12 | 1 | NM_016123.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 151984Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251156Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135764
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1458716Hom.: 0 Cov.: 30 AF XY: 0.0000207 AC XY: 15AN XY: 725618
GnomAD4 genome ? AF: 0.0000855 AC: 13AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74358
ClinVar
Submissions by phenotype
Immunodeficiency 67 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gain c.547C>T (p.Arg183Ter) variant in IRAK4 gene has been reported previously in individuals affected with IRAK4 deficiency (Picard et al. 2010; Yamamoto et al. 2014). This variant is reported with an allele frequency of 0.002% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic, but no details for independent assessment. The nucleotide change c.547C>T in IRAK4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation, leading to a smaller protein than the wild-type (Yamamoto et al. 2014). Loss of function variants in IRAK4 gene have been previously reported to be disease causing. Additional functional studies are required to prove the pathogenicity of this variant, for these reasons, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change creates a premature translational stop signal (p.Arg183*) in the IRAK4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IRAK4 are known to be pathogenic (PMID: 17893200, 21057262). This variant is present in population databases (rs114951157, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with IRAK4 deficiency (PMID: 21057262). ClinVar contains an entry for this variant (Variation ID: 567326). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at