Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_016222.4 | MANE Select | 2099 nt | 17–1885 |
| NM_016222.2 | Alternative | 2118 nt | 22–1890 |
| NM_016222.3 | Alternative | 2478 nt | 382–2250 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis sequence change affects a donor splice site in intron 6 of the DDX41 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DDX41 are known to be pathogenic (PMID: 26712909, 27133828). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DDX41-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.14 | -323 bp |
| Donor Loss (DL) | 1.0 | 1 bp |
| Acceptor Gain (AG) | 0.0 | 382 bp |
| Donor Gain (DG) | 0.42 | 49 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease'. The evidence for this variant shows: it affects the canonical +1 splice donor site, predicted to abolish normal splicing, and DDX41 loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because the variant is a canonical splice site change in a gene with established loss-of-function pathogenicity.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: it is a splice site change, not a missense altering the same codon as a known pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no de novo data or parental testing is available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to controls'. The evidence for this variant shows: no case-control or prevalence data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain without benign variation'. The evidence for this variant shows: no information on hotspot or critical domain involvement. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium'. The evidence for this variant shows: it is not present in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from large population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant'. The evidence for this variant shows: inheritance and phase data are not available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants'. The evidence for this variant shows: it is a splice site change, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before'. The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease'. The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is a splice site variant. Therefore, this criterion is not applied.
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)'. The evidence for this variant shows: SpliceAI predicts a maximal donor loss score of 1.0 indicating high likelihood of splice disruption, despite a low CADD score. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a damaging splicing effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no specific phenotype or clinical presentation data provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation'. The evidence for this variant shows: ClinVar lists it as Likely Pathogenic by one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable database reports a pathogenic interpretation without accessible primary evidence.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium'. The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder'. The evidence for this variant shows: it is not present in population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a recessive (homozygous) or dominant (heterozygous) disease with full penetrance at an early age'. The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional studies have been conducted. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease'. The evidence for this variant shows: it is a splice variant, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or in cis with a pathogenic variant'. The evidence for this variant shows: no phase information. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without a known function'. The evidence for this variant shows: it is a splice site alteration. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: SpliceAI predicts high impact despite a low CADD score, overall supporting a damaging effect. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate diagnosis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation'. The evidence for this variant shows: no benign assertions in reputable sources. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing and no conservation of nucleotide'. The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.