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 creates a premature translational stop signal (p.Ala500Argfs*52) in the DDX41 gene. It is expected to result in an absent or disrupted protein product. 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. ClinVar contains an entry for this variant (Variation ID: 4010358). For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The DDX41 A500Rfs*52 variant is a truncating mutation that results in the loss of protein function. Functional studies, including in vivo experiments with zebrafish, demonstrate that this mutation is inactivating, leading to increased proliferation of hematopoietic stem and progenitor cells. This supports a damaging effect of the variant, consistent with its association with hematopoietic malignancies.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.04 | -132 bp |
| Donor Loss (DL) | 0.01 | -491 bp |
| Acceptor Gain (AG) | 0.01 | 0 bp |
| Donor Gain (DG) | 0.02 | -223 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: c.1480_1496dup causes a frameshift (A500Rfs*52) leading to a premature stop codon and predicted loss of function; DDX41 loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a gene where LOF causes disease.
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 frameshift duplication, not the same amino acid substitution as any 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 are available. Therefore, this criterion is not applied.
PS3 (Strong)
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: in vivo zebrafish experiments demonstrate that A500Rfs*52 is inactivating, leading to increased proliferation of hematopoietic stem and progenitor cells. Therefore, this criterion is applied at Strong strength because functional studies demonstrate a damaging effect.
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 with controls.' The evidence for this variant shows: no case‐control data or statistical enrichment analysis 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 specific hotspot or critical domain annotation is provided. 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 (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
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: DDX41 is associated with dominant predisposition and there is no data on trans configuration. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in‐frame deletions/insertions in a non‐repetitive region or stop‐loss variants.' The evidence for this variant shows: it is a frameshift leading to a truncated protein, already captured by PVS1. 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 a frameshift, not a missense alteration. 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 data are available. 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 are 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 that has 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 frameshift, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
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.' The evidence for this variant shows: computational tools are not informative for frameshifts and SpliceAI score is low; no consensus of deleterious computational predictions. Therefore, this criterion is not applied.
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 detailed phenotype or family history is 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 this variant as Pathogenic by two clinical laboratories. Therefore, this criterion is applied at Supporting strength because it is reported pathogenic by a reputable source without primary data.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is greater than 5% in population databases.' The evidence for this variant shows: allele frequency is 0% in gnomAD. 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 the disorder.' The evidence for this variant shows: allele frequency is 0%. 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 with full penetrance expected at an early age.' The evidence for this variant shows: no such observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well‐established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: functional studies demonstrate a damaging effect. 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 are available. 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 truncating variant itself. 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 in any gene.' The evidence for this variant shows: no phasing data are available. 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 frameshift duplication not confined to a repetitive region. 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: computational evidence for a frameshift is not relevant; no significant splicing impact predicted. 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 molecular diagnosis is 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 evidence not available to the laboratory.' The evidence for this variant shows: no benign assertions are reported. 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 evolutionary conservation.' The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.