DDX41 c.1480_1496dup, p.Ala500ArgfsTer52
NM_016222.2:c.1480_1496dup
Pathogenic
This DDX41 frameshift variant c.1480_1496dup (A500Rfs*52) creates a premature stop codon in a gene where loss of function is a known mechanism (PVS1 Very Strong), is absent from controls (PM2 Moderate), has strong functional evidence of damaging effect (PS3 Strong), and is reported as pathogenic in ClinVar (PP5 Supporting). No benign criteria apply. Combined evidence supports a classification of Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
Genetic Information
Gene & Transcript Details
Gene
DDX41
Transcript
NM_016222.4
MANE Select
Total Exons
17
Strand
Reverse (−)
Reference Sequence
NC_000005.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_016222.2 | Alternative | 17 exons | Reverse |
| NM_016222.3 | Alternative | 17 exons | Reverse |
Variant Details
HGVS Notation
NM_016222.2:c.1480_1496dup
Protein Change
A500Rfs*52
Location
Exon 14
(Exon 14 of 17)
5'Exon Structure (17 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 500 in gene DDX41
Variant interpretation based on transcript NM_016222.4
Genome Browser
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HGVS InputNM_016222:c.1480_1496dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This 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.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 500 in gene DDX41
Functional Summary
The DDX41 A500Rfs*52 variant is a truncating mutation that results in loss of protein function. Functional studies, including in vivo experiments with zebrafish, demonstrate that this truncating mutation leads to increased proliferation of hematopoietic stem and progenitor cells, supporting a damaging effect consistent with its role in hematopoietic malignancies.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
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/multiexon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: c.1480_1496dupAAGGGCCTGGACTTCCC generates a frameshift (A500Rfs*52) predicted to result in loss of function, and DDX41 is known to be disease‐associated via loss of function. Therefore, this criterion is applied at Very Strong strength because this truncating variant is a null variant in a gene where LOF is a known mechanism.
PS1
PS1 (Not Applied) Strength Modified
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 resulting in a novel termination, not the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
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 information on parental testing or de novo status. Therefore, this criterion is not applied.
PS3
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: zebrafish in vivo functional studies demonstrate that the A500Rfs*52 truncating mutation leads to increased proliferation of hematopoietic stem and progenitor cells, consistent with damaging effect. Therefore, this criterion is applied at Strong strength.
PS4
PS4 (Not Applied) Strength Modified
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 published case-control or cohort data quantifying enrichment in affected versus controls. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
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 data on domain or hotspot location in DDX41. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases." The evidence for this variant shows: it is absent from gnomAD, 1000 Genomes, and ESP. Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied) Strength Modified
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‐related disease is not established as recessive with compound heterozygosity, and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it is a frameshift duplication leading to premature stop, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data are provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data in families. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and pathogenic missense variants are common." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
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: in silico splicing prediction (SpliceAI max 0.04) is below significance, and frameshift impact is covered by PVS1. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
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 phenotype or clinical presentation data. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic but evidence not available for independent evaluation." The evidence for this variant shows: ClinVar entries from two clinical laboratories classify it as Pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency greater than expected for disorder." The evidence for this variant shows: allele frequency is 0%, below any threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals with full penetrance expected at an early age." The evidence for this variant shows: no data on healthy carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function." The evidence for this variant shows: functional studies show damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant." The evidence for this variant shows: no data on phasing with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift duplication, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
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 splicing prediction is benign but variant is a frameshift covered by PVS1. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
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 cause reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence not available." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact and low evolutionary conservation." The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.