Classification rationale

PM2 BP4 VUS

DDX41 c.521A>G

The DDX41 c.521A>G (p.Asp174Gly, p.D174G) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.² No reviewed variant-specific functional study was identified for this variant.³ Available computational evidence argues against a damaging effect, with SpliceAI showing no significant splice impact (max delta score 0.14), REVEL 0.124, and BayesDel -0.387301.⁴

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗

4 spliceai ↗revelbayesdel

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 · 18 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

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in the general population and meets PM2 at supporting strength.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Multiple computational predictors argue against a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.14, REVEL is low at 0.124, and BayesDel is negative at -0.387301, supporting BP4.

SpliceAI max delta score 0.14 indicates no significant splice impact.REVEL score 0.124 is low.BayesDel score -0.387301 is negative.

spliceai ↗

Assessed · not applied · 3 not met · 15 not assessed

Pathogenic

PS1 No evidence was identified showing that another nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic classification.

PS2 No confirmed de novo occurrence was identified for this variant.

PS3 No well-established functional study was identified for p.(Asp174Gly) demonstrating a damaging effect on DDX41 function.

PS4 No case-control enrichment data or multiple affected probands carrying this specific variant were identified.

PM1 Available evidence does not show that Asp174 lies in a well-established mutational hotspot or a defined critical functional region without benign variation.

PM6 No apparently de novo occurrence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified showing that this variant tracks with DDX41-related hematologic malignancy predisposition in affected relatives.

PP2 Available evidence does not establish a gene-specific rule that missense variation is a common pathogenic mechanism for DDX41 and that benign missense variation is uncommon.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No individual clinical phenotype or family history data were provided to determine whether the presentation is highly specific for DDX41-related disease.

Benign

BA1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore below the stand-alone benign frequency threshold of 1%.

BS1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore below the strong benign frequency threshold of 0.3%.

BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency sufficient to argue against pathogenicity.

BS3 No well-established functional study was identified showing normal DDX41 function for p.(Asp174Gly).

BS4 No non-segregation data were identified for this variant.

BP1 Available evidence does not establish that missense variation is generally a benign or uncommon disease mechanism in DDX41 sufficient to support BP1 for this missense change.

BP2 No phase information or second-variant data were identified to assess occurrence in trans with a pathogenic variant or in cis with another variant.

BP5 No alternate molecular diagnosis or alternate established cause for the observed phenotype was provided to support BP5.

N/A · 8 PVS1 · PM3 · PM4 · PM5 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.124. BayesDel score = -0.387301.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. DDX41, an RNA helicase involved in innate immunity, is recurrently altered by mutation in hematopoietic malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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