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DDX41c.1480_1496dupLikely pathogenic
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Variant interpretation report

DDX41 c.1480_1496dup, p.(Ala500ArgfsTer52)

NM_016222.2:c.1480_1496dup NP_057306.2:p.(Ala500ArgfsTer52) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About DDX41

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen DDX41 VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong

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.

PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ACMG/AMP qualitative combination: PVS1_Strong + PM2_Supporting

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,461,874 alleles

gnomAD v4.1: 1 / 1,461,874 alleles. Recorded AF 6.84053e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only
For specialists

Technical detail

ACMG/AMP criteria under ClinGen DDX41 VCEP v1.0.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 2 not met · 14 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

Met · 2

PVS1 StrongNM_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. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1, downgraded for terminal-exon truncation expected to escape NMD.
Evidence considered
  • Predicted consequence p.(Ala500ArgfsTer52)/p.(A500Rfs*52)
  • Variant lies in exon 14/last exon
  • OncoKB lists likely loss-of-function biological effect
  • Published DDX41 literature supports loss-of-function disease mechanism
Still missing
  • No DDX41-specific local criteria text was retrievable from the supplied VCEP folder, so PVS1 strength was assigned using generic ACMG loss-of-function logic.
Sources
oncokb ↗PMID:26712909 ↗PMID:36322930 ↗
PM2 SupportingThe 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. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2 at Supporting strength for a very rare heterozygous variant in a dominant predisposition gene.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 total AF 6.84053e-07; NFE AF 8.99276e-07
Still missing
  • No retrievable DDX41-specific PM2 threshold text was available in the supplied local VCEP folder.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 2 · evaluated, threshold not reached

BA1 The observed gnomAD v4.1 AF of 6.84053e-07 is far below any stand-alone benign frequency threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF 6.84053e-07
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF values
Sources
gnomad_v4 ↗

Not assessed · 14 · no assessment recorded

PS1 No same-amino-acid pathogenic variant comparison was documented for this frameshift duplication. Details ▾Hide ▴
Still missing
  • A curated same-protein-consequence comparison was not provided in the workspace.
PS2 No confirmed de novo data were provided. Details ▾Hide ▴
Still missing
  • Parental testing/confirmation data unavailable.
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. Details ▾Hide ▴
Evidence considered
  • General DDX41 functional literature
Still missing
  • No variant-specific functional assay result in the supplied workspace.
Sources
PMID:33651979 ↗PMID:36322930 ↗
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. Details ▾Hide ▴
Evidence considered
  • ClinVar pathogenic submissions
Still missing
  • Variant-specific case counts and ascertainment details not assembled.
Sources
clinvar ↗
PM5 PM5 is not informative for this frameshift duplication. Details ▾Hide ▴

No further detail was recorded.

PM6 No assumed de novo evidence was provided. Details ▾Hide ▴
Still missing
  • Family-based testing data unavailable.
PP1 No segregation data were provided. Details ▾Hide ▴
Still missing
  • Pedigree and segregation information unavailable.
PP4 No phenotype-specific case data were provided for the tested individual. Details ▾Hide ▴
Still missing
  • Clinical phenotype and family history details unavailable.
BS2 No evidence of the variant in well-phenotyped unaffected adults was provided. Details ▾Hide ▴
Still missing
  • Unaffected carrier data unavailable.
BS3 No variant-specific well-established functional studies demonstrating normal function were provided. Details ▾Hide ▴
Evidence considered
  • Only gene-level functional literature was screened
Still missing
  • No normal-function assay for this exact variant in the workspace.
Sources
PMID:33651979 ↗
BS4 No segregation-against-disease data were provided. Details ▾Hide ▴
Still missing
  • Family segregation data unavailable.
BP2 No phase data or second pathogenic variant data were provided. Details ▾Hide ▴
Still missing
  • Phase and additional-variant data unavailable.
BP3 No evidence indicates that this duplication lies within a benign repetitive region without known function. Details ▾Hide ▴
Still missing
  • Region-specific benign repeat annotation unavailable.
BP5 No alternate molecular explanation for the phenotype was provided. Details ▾Hide ▴
Still missing
  • Clinical and genotype context insufficient for BP5 assessment.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 N/AThis is a truncating frameshift variant, and the workspace did not identify a statistically significant hotspot at residue Ala500. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots search reported no hotspot row
PM3 N/APM3 is not applicable for this autosomal dominant disorder context. Details ▾Hide ▴
Evidence considered
  • Disease context is autosomal dominant DDX41-related hematologic malignancy predisposition syndrome
Sources
cspec ↗
PM4 N/APM4 was not applied because the protein-length altering effect is already captured by PVS1 for this loss-of-function frameshift. Details ▾Hide ▴
Evidence considered
  • Frameshift with premature termination
PP2 N/APP2 is a missense-focused criterion and is not applicable to this frameshift duplication. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 was not applied because this is a frameshifting duplication rather than a missense or splice-region variant with interpretable in silico thresholds in the workspace. Details ▾Hide ▴
Evidence considered
  • Non-SNV frameshift duplication
Still missing
  • No SpliceAI result was captured in the supplied files.
PP5 N/APP5 was not used because reputable-source assertions are not applied as independent evidence under current ClinGen practice. Details ▾Hide ▴
Evidence considered
  • ClinVar pathogenic classification noted but not counted as PP5
Sources
clinvar ↗
BP1 N/ABP1 is a missense-specific benign criterion and is not applicable to this truncating frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 was not applied because this is a frameshifting duplication and no benign in silico evidence was provided. Details ▾Hide ▴
Still missing
  • No applicable in silico benign prediction result in the workspace.
BP6 N/ABP6 was not used because external assertions without shared evidence are not applied as independent evidence under current ClinGen practice. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 is a synonymous/intronic criterion and is not applicable to this coding frameshift duplication. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
DDX41
Transcript
NM_016222.2
Coding (HGVS c.)
NM_016222.2:c.1480_1496dup
Protein (HGVS p.)
NP_057306.2:p.(Ala500ArgfsTer52)
GRCh38
chr5:177512548 A>AGGGAAGTCCAGGCCCTT
GRCh37
chr5:176939549 A>AGGGAAGTCCAGGCCCTT

Gene diagram

Every interpreted variant in DDX41, mapped onto the exon structure of NM_016222.2. Select a row to find it on the plot.

DDX41NM_016222.2
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,461,874 alleles AF 6.84e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.8e-07 · 1 / 1,461,874 alleles · 0 hom
European (non-Finnish)1 / 1,112,006 9e-07
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, African/African American.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 was not applied because this is a frameshifting duplication rather than a missense or splice-region variant with interpretable in silico thresholds in the workspace. Details ▾Hide ▴
Evidence considered
  • Non-SNV frameshift duplication
Still missing
  • No SpliceAI result was captured in the supplied files.
BP4 N/ABP4 was not applied because this is a frameshifting duplication and no benign in silico evidence was provided. Details ▾Hide ▴
Still missing
  • No applicable in silico benign prediction result in the workspace.
BP7 N/ABP7 is a synonymous/intronic criterion and is not applicable to this coding frameshift duplication. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,461,874 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record
Cancer hotspots Captured Cancer Hotspots source record
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

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.

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).