DDX41 c.260T>A, p.Leu87His
NM_016222.2:c.260T>A
Variant of Uncertain Significance (VUS)
The variant p.L87H in DDX41 is absent from population databases (PM2) and predicted computationally benign (BP4), with no additional supporting or contradicting evidence; thus it remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
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.260T>A
Protein Change
L87H
Location
Exon 3
(Exon 3 of 17)
5'Exon Structure (17 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 87 in gene DDX41
Variant interpretation based on transcript NM_016222.4
Genome Browser
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HGVS InputNM_016222:c.260T>A
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 87 in gene DDX41
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.537
0.537
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
No
Additional Predictors
Benign:
CADD: 5.37
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, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (c.260T>A, p.L87H), not a null variant. Therefore, this criterion is not applied.
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: there is no previously established pathogenic variant causing the same p.L87H amino acid change. Therefore, this criterion is not applied.
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 reports of confirmed de novo occurrence. Therefore, this criterion is not applied.
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 studies have been performed. Therefore, this criterion is not applied.
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 with the prevalence in controls." The evidence for this variant shows: no case-control data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied.
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 location in a mutational hotspot or critical domain. Therefore, this criterion is not applied.
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: the variant is absent from population databases including gnomAD (MAF = 0%). Therefore, this criterion is applied at Moderate strength.
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: no report of recessive biallelic findings. Therefore, this criterion is not applied.
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 a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a missense substitution with no change in protein length. Therefore, this criterion is not applied.
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 at codon 87 has been reported. Therefore, this criterion is not applied.
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 de novo assumption data available. Therefore, this criterion is not applied.
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. Therefore, this criterion is not applied.
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 missense variants a common mechanism of disease." The evidence for this variant shows: DDX41 has both LOF and missense reported; insufficient data to confirm low benign missense rate. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
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: computational predictions are mixed (CADD 5.37 benign, REVEL 0.54 below pathogenic threshold, SpliceAI 0.01 no splicing impact). Therefore, this criterion is not applied.
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 phenotype or family history data provided. Therefore, this criterion is not applied.
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: not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >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.
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%, not greater than expected. Therefore, this criterion is not applied.
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 reported. Therefore, this criterion is not applied.
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 performed. Therefore, this criterion is not applied.
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.
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: while DDX41 LOF is a known mechanism, missense variants have been reported. Therefore, this criterion is not applied.
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 fully penetrant dominant gene/disorder, or in cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)." The evidence for this variant shows: mixed in silico results with CADD 5.37, REVEL 0.54, and SpliceAI 0.01 indicating no significant impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: no such reports in ClinVar or elsewhere. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "A synonymous (silent) variant for which splicing prediction algorithms predict no impact on the splice consensus sequence nor the creation of a new splice site." The evidence for this variant shows: it is a missense variant, not synonymous. Therefore, this criterion is not applied.