DDX41 c.962C>G, p.Pro321Arg
NM_016222.2:c.962C>G
Variant of Uncertain Significance (VUS)
The DDX41 NM_016222.2:c.962C>G (P321R) variant remains a Variant of Uncertain Significance (VUS) based on application of PM2 (Moderate) for absence in population databases and PP3 (Supporting) for deleterious computational predictions, with no available functional, segregation, case-control, or other evidence to reach a definitive pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
DDX41
Transcript
NM_016222.4
MANE Select
Total Exons
17
Strand
Reverse (−)
Reference Sequence
NC_000005.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_016222.2 | Alternative | 17 exons | Reverse |
| NM_016222.3 | Alternative | 17 exons | Reverse |
Variant Details
HGVS Notation
NM_016222.2:c.962C>G
Protein Change
P321R
Location
Exon 10
(Exon 10 of 17)
5'Exon Structure (17 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 321 in gene DDX41
Variant interpretation based on transcript NM_016222.4
Genome Browser
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HGVS InputNM_016222:c.962C>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 321 in gene DDX41
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.769
0.769
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Benign:
CADD: 5.51
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows: it is a missense change (P321R), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is a missense change and does not result in loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant with the P321R amino acid change at this position. Therefore, this criterion is not applied at Not Applied strength because no known pathogenic variant shares the same amino acid substitution.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo status information is available. Therefore, this criterion is not applied at Not Applied strength because parental origin has not been assessed.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional characterization of P321R has been performed. Therefore, this criterion is not applied at Not Applied strength because functional study data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The evidence for this variant shows: no case-control or affected individual prevalence data are available. Therefore, this criterion is not applied at Not Applied strength because no prevalence data exist.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation." The evidence for this variant shows: no data indicating that residue P321 lies within a known mutational hotspot or critical functional domain. Therefore, this criterion is not applied at Not Applied strength because hotspot/domain information is not provided.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium." The evidence for this variant shows: it is absent from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is not observed in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: DDX41-related disease is autosomal dominant and no trans allele information is available. Therefore, this criterion is not applied at Not Applied strength because PM3 is not relevant for dominant inheritance and no trans data exist.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat region or stop-loss variants." The evidence for this variant shows: it is a missense substitution without any change in protein length. Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: no other pathogenic missense variant has been reported at residue 321. Therefore, this criterion is not applied at Not Applied strength because no pathogenic missense at this position is known.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no information on de novo occurrence. Therefore, this criterion is not applied at Not Applied strength because de novo status is not assessed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied at Not Applied strength because segregation has not been evaluated.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: gene‐specific missense constraints for DDX41 are not characterized. Therefore, this criterion is not applied at Not Applied strength because the gene’s missense tolerance is not established.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)." The evidence for this variant shows: REVEL score of 0.77 (>0.75 threshold) supports deleterious effect; CADD score 5.51 and SpliceAI show no benign evidence. Therefore, this criterion is applied at Supporting strength because in silico tools predict a damaging impact.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no specific phenotype or family history data provided. Therefore, this criterion is not applied at Not Applied strength because clinical specificity cannot be assessed.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: it is not present in ClinVar or other reputable sources. Therefore, this criterion is not applied at Not Applied strength because no external pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is greater than 5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength because frequency is well below the threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at Not Applied strength because frequency does not exceed expected disease threshold.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age." The evidence for this variant shows: no such observations in healthy individuals. Therefore, this criterion is not applied at Not Applied strength because no healthy adult carrier data exist.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation has not been assessed.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: DDX41 disease mechanism is primarily loss-of-function but missense pathogenicity is not established. Therefore, this criterion is not applied at Not Applied strength because gene‐specific missense mechanism is unclear.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a recessive disorder, or in cis with a pathogenic variant in any disorder." The evidence for this variant shows: no data on cis/trans with other variants. Therefore, this criterion is not applied at Not Applied strength because no such observations exist.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in a repetitive region without a known function." The evidence for this variant shows: it is a missense substitution, not an indel. Therefore, this criterion is not applied at Not Applied strength because not applicable.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: computational tools predict deleterious effect. Therefore, this criterion is not applied at Not Applied strength because in silico evidence supports pathogenicity.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternative molecular basis of disease." The evidence for this variant shows: no alternative molecular diagnosis is described. Therefore, this criterion is not applied at Not Applied strength because no other etiology is identified.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied at Not Applied strength because no reputable benign assertion is available.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous (silent) variant with no predicted splicing impact." The evidence for this variant shows: it is a missense substitution, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant type is not applicable.