NM_016222.2:c.1480_1496dup is a frameshifting duplication predicted to produce p.(Ala500ArgfsTer52) [p.(A500Rfs*52)], altering the reading frame from codon 500 and truncating the normal C-terminal portion of DDX41; this is consistent with a loss-of-function effect in a gene for which loss of function has been implicated in DDX41-related hematologic malignancy predisposition syndrome.1 The variant is absent from gnomAD v2.1 and is seen once in gnomAD v4.1 at AF 6.84053e-07 (1/1,461,874 alleles), with highest observed population AF 8.99276e-07 in non-Finnish Europeans, supporting marked rarity in population databases.2 Because the predicted premature termination occurs in the terminal exon, the available loss-of-function evidence is most appropriately weighted below full very-strong strength, and no additional independently curated case-level or functional evidence in the supplied materials upgrades the variant beyond the likely pathogenic range. Overall, the available evidence supports classification of NM_016222.2:c.1480_1496dup (DDX41 p.(Ala500ArgfsTer52)) as Likely Pathogenic.3
Final classification
Likely Pathogenic
PVS1PM2
DDX41
c.1480_1496dup
p.Ala500ArgfsTer52
This variant
NM_016222.2:c.1480_1496dup is a frameshifting duplication predicted to produce p.(Ala500ArgfsTer52) [p.(A500Rfs*52)], altering the reading frame from codon 500 and truncating the normal C-terminal portion of DDX41; this is consistent with a loss-of-function effect in a gene for which loss of function has been implicated in DDX41-related hematologic malignancy predisposition syndrome.
ACMG/AMP qualitative combination: PVS1_Strong + PM2_Supporting
Classification rationale
PVS1PM2
Likely Pathogenic
DDX41 c.1480_1496dup
PVS1 + PM2
→
Likely Pathogenic
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_016222.2 · variants mapped to exon structure
DDX41
NM_016222.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
strong
review
Pathogenic
NM_016222.2:c.1480_1496dup is a frameshifting duplication predicted to produce p.(Ala500ArgfsTer52)/p.(A500Rfs*52). VariantValidator places the change in exon 14, the last exon, so nonsense-mediated decay is not expected; however, the variant removes and replaces a substantial C-terminal portion of the normal protein. DDX41 loss of function is an established disease mechanism for DDX41-related hematologic malignancy predisposition, so generic ACMG PVS1 is applicable but conservatively downgraded to Strong for a terminal-exon truncating event.
Predicted consequence p.(Ala500ArgfsTer52)/p.(A500Rfs*52)Variant lies in exon 14/last exonOncoKB lists likely loss-of-function biological effect
PM2
supporting
review
Pathogenic
The variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 at AF 6.84053e-07 (1/1,461,874 alleles), with highest observed population AF 8.99276e-07 in non-Finnish Europeans; this supports rarity and is well below generic ACMG rarity cutoffs.
gnomAD v2.1 absentgnomAD v4.1 total AF 6.84053e-07; NFE AF 8.99276e-07
Assessed · not applied
· 2 not met · 14 not assessed
Pathogenic
PS1
No same-amino-acid pathogenic variant comparison was documented for this frameshift duplication.
PS2
No confirmed de novo data were provided.
PS3
The screened functional literature supports DDX41 biology but does not provide a variant-specific, well-established functional assay for NM_016222.2:c.1480_1496dup.
PS4
ClinVar lists the variant as Pathogenic, but the workspace does not provide independently curated proband counts or case-control data sufficient to score PS4.
PM5
PM5 is not informative for this frameshift duplication.
PM6
No assumed de novo evidence was provided.
PP1
No segregation data were provided.
PP4
No phenotype-specific case data were provided for the tested individual.
Benign
BA1
The observed gnomAD v4.1 AF of 6.84053e-07 is far below any stand-alone benign frequency threshold.
BS1
The observed gnomAD v4.1 AF of 6.84053e-07 and highest population AF of 8.99276e-07 are far below benign strong frequency ranges.
BS2
No evidence of the variant in well-phenotyped unaffected adults was provided.
BS3
No variant-specific well-established functional studies demonstrating normal function were provided.
BS4
No segregation-against-disease data were provided.
BP2
No phase data or second pathogenic variant data were provided.
BP3
No evidence indicates that this duplication lies within a benign repetitive region without known function.
BP5
No alternate molecular explanation for the phenotype was provided.
N/A · 10
PM1 · PM3 · PM4 · PP2 · PP3 · PP5 · BP1 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.84053e-07; MAF= 0.00007%, 1/1461874 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.99276e-07; MAF= 0.00009%, 1/1112006 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.8e-05%
· 1 / 1,461,874
0 hom
0 hom
European (non-Finnish) 1 / 1,112,006 |
9e-05% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Novel germ line DDX41 mutations define families with a lower age of MDS/AML onse
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Germ line DDX41 mutations define a unique subtype of myeloid neoplasms.
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Sources & reference links