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DDX41c.1589G>AUncertain significance
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Variant interpretation report

DDX41 c.1589G>A, p.(Gly530Asp)

NM_016222.2:c.1589G>A NP_057306.2:p.(Gly530Asp) View identifiers
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.

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
PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the 0.1% rarity threshold used for PM2 support in this workflow and is consistent with rarity in the general population.

PP3Supporting
PP3 · supporting

Computational evidence supports a deleterious protein effect for this missense change: REVEL is 0.901, while SpliceAI shows no meaningful splice disruption with a maximum delta score of 0.03. Taken together, these data support PP3 for a damaging missense effect rather than a splice mechanism.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Generic ACMG/AMP final classification combination rules (PMID:25741868) were applied because the retrieved DDX41 ClinGen Myeloid Malignancy specification did not provide a complete usable final-classification rule set.

02The sources

Evidence at a glance

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

No screenshot for this evidence
Computational predictions
Not recorded

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

Applied · PP3 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 Cancer Hotspots ↗
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 · 5 not met · 14 not assessed · 7 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

The DDX41 c.1589G>A (p.Gly530Asp) variant has been observed in somatic cancers in COSMIC (COSV57250947, 4 occurrences) and has been reported in ClinVar as a variant of uncertain significance from 4 clinical laboratory submissions.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population.

In silico data support a damaging missense effect, with a REVEL score of 0.901, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.03.

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, corresponding to an observed population frequency of 0, which is below the 0.1% rarity threshold used for PM2 support in this workflow and is consistent with rarity in the general population. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingComputational evidence supports a deleterious protein effect for this missense change: REVEL is 0.901, while SpliceAI shows no meaningful splice disruption with a maximum delta score of 0.03. Taken together, these data support PP3 for a damaging missense effect rather than a splice mechanism. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • REVEL score 0.901
  • SpliceAI max delta score 0.03
Sources
spliceai ↗prefetch

Not met · 5 · evaluated, threshold not reached

PS4 This variant has been observed in somatic cancers in COSMIC (COSV57250947, n=4) and is listed in ClinVar as Uncertain significance, but no case-control enrichment or clearly quantified excess in unrelated individuals with DDX41-related hematologic malignancy predisposition was identified, so PS4 is not met. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • COSMIC COSV57250947 somatic count 4
  • ClinVar: Uncertain significance, 4 clinical laboratories
Still missing
  • Variant-specific affected versus control enrichment data
  • Independent germline case counts with denominator data
Sources
cosmicclinvar ↗PMID:26712909 ↗PMID:34644397 ↗PMID:37199125 ↗267129093464439737199125
PM1 This variant has not been shown to lie in a well-established mutational hotspot or a critical domain without benign variation; Cancer Hotspots did not identify a statistically significant hotspot at residue G530, so PM1 is not met. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Cancer Hotspots: no significant hotspot row identified for DDX41 G530
  • Exact variant not listed in hotspot results
Still missing
  • Gene-specific domain or hotspot evidence showing Gly530 is a critical constrained residue
Sources
hotspots ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed population frequency of 0, which is below the 1% threshold required for BA1, so BA1 is not met. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed population frequency of 0, which is below the 0.3% threshold used for BS1 in this workflow, so BS1 is not met. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Computational data do not support a benign effect overall. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, REVEL is 0.901 and supports a damaging missense effect, so BP4 is not met. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • REVEL score 0.901
  • SpliceAI max delta score 0.03
Sources
spliceai ↗prefetch

Not assessed · 14 · no assessment recorded

PS1 No evidence was identified that a different nucleotide change causing the same amino acid substitution, p.(Gly530Asp), is already established as pathogenic or likely pathogenic, so PS1 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • ClinVar entry for this variant is Uncertain significance
Still missing
  • Variant-level comparison against known pathogenic alternate codon changes at Gly530
Sources
clinvar ↗
PS2 No confirmed de novo occurrence with established maternity and paternity was identified, so PS2 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Still missing
  • Trio-based de novo data
PS3 No well-established functional study demonstrating a damaging effect of p.(Gly530Asp) on DDX41 function was identified, so PS3 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Reviewed DDX41 literature did not provide a validated variant-specific functional result for p.(Gly530Asp)
Still missing
  • Validated variant-specific functional assay data
Sources
PMID:26712909 ↗PMID:34644397 ↗PMID:37199125 ↗267129093464439737199125
PM5 No evidence was identified that a different missense change at codon 530 is already established as pathogenic or likely pathogenic, so PM5 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • ClinVar records retrieved for this variant do not establish PM5
Still missing
  • Codon-level review of other pathogenic missense variants affecting Gly530
Sources
clinvar ↗
PM6 No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Still missing
  • Probable de novo case data
PP1 No segregation data were identified showing this variant tracking with DDX41-related hematologic malignancy predisposition in a family, so PP1 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Reviewed literature did not provide usable segregation evidence for p.(Gly530Asp)
Still missing
  • Family segregation data with informative meioses
Sources
PMID:26712909 ↗PMID:34644397 ↗PMID:37199125 ↗267129093464439737199125
PP2 Available evidence was insufficient to determine whether missense variation is a well-established pathogenic mechanism for DDX41 with a sufficiently low benign missense rate to support PP2, so PP2 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • No retrievable criterion-level DDX41 VCEP rule for PP2 was available
Still missing
  • Gene-level missense constraint and mechanism evidence specific to DDX41
Sources
cspec ↗
PP4 No individual-level phenotype, tumor, or family history details were identified that are sufficiently specific for DDX41-related hematologic malignancy predisposition to support PP4, so PP4 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Still missing
  • Detailed phenotype and family history for the tested individual
BS2 No evidence was identified showing this variant in well-phenotyped healthy adults at a frequency sufficient to argue against pathogenicity, so BS2 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Variant absent from gnomAD
Still missing
  • Presence in unaffected older adults with relevant clinical context
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study demonstrating normal DDX41 function for p.(Gly530Asp) was identified, so BS3 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Reviewed literature did not provide a variant-specific normal-function result for p.(Gly530Asp)
Still missing
  • Validated benign functional assay data
Sources
PMID:26712909 ↗PMID:34644397 ↗PMID:37199125 ↗267129093464439737199125
BS4 No segregation data were identified showing lack of cosegregation of this variant with disease in informative relatives, so BS4 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Still missing
  • Informative family nonsegregation data
BP1 Available evidence was insufficient to conclude that missense variation is an uncommon disease mechanism for DDX41 relative to truncating variants, so BP1 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • No retrievable criterion-level DDX41 rule supporting BP1
Still missing
  • Gene-level evidence showing missense is a minor mechanism in DDX41
Sources
cspec ↗
BP3 No evidence was identified that this amino acid change falls within a repetitive region or a region without known function where in-frame variation is typically tolerated, so BP3 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Still missing
  • Protein-region evidence showing Gly530 lies in a tolerated repetitive or low-complexity region
BP5 No alternate molecular explanation was identified that would account for the phenotype independently of this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
generic_acmg_fallback
Still missing
  • Case-level alternate diagnosis data
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, p.(Gly530Asp), and does not create a predicted null effect such as a nonsense, frameshift, canonical splice, initiation-codon, or exon-level loss-of-function change, so PVS1 is not applicable. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • NM_016222.2:c.1589G>A
  • NP_057306.2:p.(Gly530Asp)
  • DDX41-related hematologic malignancy predisposition syndrome is autosomal dominant
Sources
prefetchcspec ↗
PM3 N/AThe available disease framework for DDX41-related hematologic malignancy predisposition is autosomal dominant, so the recessive trans observations required for PM3 are not applicable. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Preferred mode of inheritance: autosomal dominant inheritance
Sources
cspec ↗prefetch
PM4 N/AThis is a single amino acid substitution and does not produce a protein length change from an in-frame insertion, deletion, or stop-loss event, so PM4 is not applicable. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Protein consequence: p.(Gly530Asp)
Sources
prefetch
PP5 N/APP5 was not applied because assertions from external sources without independently evaluable evidence are not used for current ACMG/AMP interpretation. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • ClinVar classification available but independently reviewable evidence is preferred
Sources
clinvar ↗
BP2 N/AThe available disease framework for DDX41-related hematologic malignancy predisposition is autosomal dominant, so the recessive-phase evidence usually used for BP2 is not applicable here. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Preferred mode of inheritance: autosomal dominant inheritance
Sources
cspec ↗prefetch
BP6 N/ABP6 was not applied because external benign assertions without independently evaluable evidence are not used for current ACMG/AMP interpretation. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • ClinVar does not provide a benign or likely benign consensus for this variant
Sources
clinvar ↗
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Protein consequence: p.(Gly530Asp)
Sources
prefetch

Identifiers

Gene
DDX41
Transcript
NM_016222.2
Coding (HGVS c.)
NM_016222.2:c.1589G>A
Protein (HGVS p.)
NP_057306.2:p.(Gly530Asp)
GRCh38
chr5:177512354 C>T
GRCh37
chr5:176939355 C>T

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 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

PP3 SupportingComputational evidence supports a deleterious protein effect for this missense change: REVEL is 0.901, while SpliceAI shows no meaningful splice disruption with a maximum delta score of 0.03. Taken together, these data support PP3 for a damaging missense effect rather than a splice mechanism. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • REVEL score 0.901
  • SpliceAI max delta score 0.03
Sources
spliceai ↗prefetch
BP4 Computational data do not support a benign effect overall. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, REVEL is 0.901 and supports a damaging missense effect, so BP4 is not met. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • REVEL score 0.901
  • SpliceAI max delta score 0.03
Sources
spliceai ↗prefetch
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
generic_acmg_fallback
Evidence considered
  • Protein consequence: p.(Gly530Asp)
Sources
prefetch

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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
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

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 has been reported in ClinVar as Uncertain significance (4 clinical laboratories).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 previously been reported in somatic cancers (COSMIC; COSV57250947, n = 4 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.