About DDX41
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
DDX41 c.521A>G, p.(Asp174Gly)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
Myeloid Malignancy Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from 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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
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 · 3 not met · 15 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The DDX41 c.521A>G (p.Asp174Gly, p.D174G) variant has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.
No reviewed variant-specific functional study was identified for this variant.
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.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in the general population and meets PM2 at supporting strength. Details ▾Hide ▴
Rule
PM2_Supporting based on absence from population databases.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Rule
BP4_Supporting based on concordant benign computational evidence.
Evidence considered
- SpliceAI max delta score 0.14 indicates no significant splice impact.
- REVEL score 0.124 is low.
- BayesDel score -0.387301 is negative.
Sources
Not met · 3 · evaluated, threshold not reached
PP3 Available computational evidence does not support a deleterious 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.14.
- REVEL score 0.124.
- BayesDel score -0.387301.
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore below the stand-alone benign frequency threshold of 1%. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore below the strong benign frequency threshold of 0.3%. Details ▾Hide ▴
Not assessed · 15 · no assessment recorded
PS1 No evidence was identified showing that another nucleotide change produces the same amino acid substitution with an established pathogenic or likely pathogenic classification. Details ▾Hide ▴
PS2 No confirmed de novo occurrence was identified for this variant. Parental relationship confirmation and parental testing data were not available. Details ▾Hide ▴
PS3 No well-established functional study was identified for p.(Asp174Gly) demonstrating a damaging effect on DDX41 function. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence for this variant.
Still missing
- No variant-specific validated functional assay result was identified.
Sources
PS4 No case-control enrichment data or multiple affected probands carrying this specific variant were identified. Available evidence does not establish increased prevalence in affected individuals compared with controls. Details ▾Hide ▴
Evidence considered
- ClinVar search was negative for this variant.
- The variant is absent from gnomAD
- but no affected-case count for this exact variant was retrieved.
Still missing
- No variant-specific affected-case series or enrichment analysis was identified.
Sources
PM1 Available evidence does not show that Asp174 lies in a well-established mutational hotspot or a defined critical functional region without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue, but domain-level evidence was limited. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review did not identify a statistically significant hotspot for D174.
Still missing
- No validated gene-specific critical-region rule or residue-level hotspot evidence was identified.
Sources
PM6 No apparently de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
PP1 No segregation data were identified showing that this variant tracks with DDX41-related hematologic malignancy predisposition in affected relatives. Details ▾Hide ▴
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. Details ▾Hide ▴
Evidence considered
- The retrieved DDX41 specification did not provide an explicit PP2 rule.
Still missing
- No gene-specific missense-mechanism threshold or constraint rule was retrieved.
Sources
PP4 No individual clinical phenotype or family history data were provided to determine whether the presentation is highly specific for DDX41-related disease. Details ▾Hide ▴
Evidence considered
- Only gene- and variant-level database evidence was available.
Still missing
- Phenotype-specific case information was not available.
Sources
BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency sufficient to argue against pathogenicity. Details ▾Hide ▴
Evidence considered
- The variant is absent from both gnomAD datasets reviewed.
Still missing
- No unaffected-carrier dataset for this variant was identified.
Sources
BS3 No well-established functional study was identified showing normal DDX41 function for p.(Asp174Gly). Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- No variant-specific benign functional assay result was identified.
Sources
BS4 No non-segregation data were identified for this variant. In addition, reduced and age-related penetrance can complicate interpretation of unaffected relatives in DDX41-related disease. Details ▾Hide ▴
Evidence considered
- No family-based non-segregation evidence was retrieved.
Still missing
- No family data demonstrating lack of segregation were identified.
Sources
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. Details ▾Hide ▴
Evidence considered
- The retrieved DDX41 specification did not provide an explicit BP1 rule.
Still missing
- No gene-specific BP1 rule was retrieved.
Sources
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. Details ▾Hide ▴
Evidence considered
- No case-specific genotype context was provided.
Still missing
- No zygosity/phase data were available.
Sources
BP5 No alternate molecular diagnosis or alternate established cause for the observed phenotype was provided to support BP5. Details ▾Hide ▴
Evidence considered
- Case-specific clinical context was not available.
Still missing
- No phenotype-level differential diagnosis data were available.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not create a nonsense, frameshift, canonical ±1/2 splice, initiation-codon, or exon-level loss-of-function change. Although DDX41 loss of function is an established disease mechanism, c.521A>G does not fall within the generic PVS1 null-variant framework. Details ▾Hide ▴
Rule
Generic PVS1 fallback not applicable to this missense variant.
Evidence considered
- DDX41 loss of function is supported as a germline disease mechanism.
- NM_016222.2:c.521A>G results in p.(Asp174Gly)/p.(D174G)
- a missense substitution outside the default PVS1 variant classes.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:26712909 ↗PMID:39046192 ↗PMID:41339477 ↗PMID:30144193 ↗PMID:39357070 ↗
PM3 N/APM3 is intended for recessive disorders with pathogenic variants observed in trans. The available DDX41 disease framework is autosomal dominant, so this criterion is not applicable. Details ▾Hide ▴
Evidence considered
- The retrieved DDX41 specification lists autosomal dominant inheritance.
Sources
PM4 N/AThis variant is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event. Details ▾Hide ▴
PM5 N/AClassic same-residue PM5 logic could not be confirmed safely for the governing framework, and no pathogenic same-residue comparator variants were identified. PM5 was therefore not applied. Details ▾Hide ▴
Evidence considered
- PM5 candidate review found no same-residue comparators and could not confirm classic PM5 semantics.
Still missing
- No validated same-residue pathogenic comparator was identified.
Sources
pm5_candidatescspec ↗
PP5 N/APP5 is not applied because no reputable-source pathogenic assertion without accessible supporting evidence was used. Details ▾Hide ▴
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions without known function, which does not match this missense substitution. Details ▾Hide ▴
BP6 N/ABP6 is not applied because no reputable-source benign assertion without accessible supporting evidence was used. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splice impact. This variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- The variant is missense
- p.(Asp174Gly)
- not synonymous or intronic.
Sources
Identifiers
- Gene
- DDX41
- Transcript
- NM_016222.2
- Coding (HGVS c.)
- NM_016222.2:c.521A>G
- Protein (HGVS p.)
- NP_057306.2:p.(Asp174Gly)
- GRCh38
- chr5:177515735 T>C
- GRCh37
- chr5:176942736 T>C
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in DDX41
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Rule
BP4_Supporting based on concordant benign computational evidence.
Evidence considered
- SpliceAI max delta score 0.14 indicates no significant splice impact.
- REVEL score 0.124 is low.
- BayesDel score -0.387301 is negative.
Sources
PP3 Available computational evidence does not support a deleterious 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.14.
- REVEL score 0.124.
- BayesDel score -0.387301.
Sources
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splice impact. This variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- The variant is missense
- p.(Asp174Gly)
- not synonymous or intronic.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.124. BayesDel score = -0.387301.
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
Captured gnomAD v4.1 source record
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
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1625925053
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_016222.2%3Ac.521A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-176942736-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-177515735-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_016222.2%3Ac.521A…
- OncoKB ↗www.oncokb.org/gene/DDX41/D174G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=DDX41+c.521A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from 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.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.