DDX41 c.1099-16C>G, p.?
NM_016222.2:c.1099-16C>G
Variant of Uncertain Significance (VUS)
The DDX41 c.1099-16C>G variant is a rare intronic change with no functional, segregation, de novo, or phenotype-specific evidence to support pathogenicity or benignity. Only PM2 (absent/rare in controls) is met (Moderate), with all other criteria not applied or unevaluable, resulting in classification as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.1099-16C>G
Protein Change
?
Location
Exon 10
(Exon 10 of 17)
5'Exon Structure (17 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_016222.4
Genome Browser
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HGVS InputNM_016222:c.1099-16C>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00279%
Rare
Highest in Population
African/African American
0.00616%
Rare
Global: 0.00279%
African/African American: 0.00616%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251014Alt: 7Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00279%, 7/251014 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00616%, 1/16226 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.36
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 multiexon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is an intronic change at position -16, not affecting canonical ±1/2 splice sites. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant.
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 known amino acid change is defined for this intronic variant. Therefore, this criterion is not applied because amino acid impact is unknown and no established pathogenic variant matches.
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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied because no de novo evidence is available.
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 has been performed. Therefore, this criterion is not applied because functional study data are absent.
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 controls." The evidence for this variant shows: no case-control or patient cohort data. Therefore, this criterion is not applied because there is no evidence of increased prevalence in affected individuals.
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 without benign variation." The evidence for this variant shows: location and functional domains are not defined for this intronic change. Therefore, this criterion is not applied because hotspot or domain information is unavailable.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)." The evidence for this variant shows: MAF=0.00279% in gnomAD (7/251,014 alleles) with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
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 data on trans configuration with another pathogenic variant. Therefore, this criterion is not applied because no trans inheritance information is available.
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 or stop-loss variants." The evidence for this variant shows: no in-frame indel or protein length change. Therefore, this criterion is not applied because the variant does not alter protein length.
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." The evidence for this variant shows: no amino acid change is defined. Therefore, this criterion is not applied because no missense event can be compared.
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 data on parental origin. Therefore, this criterion is not applied because de novo status is unknown.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied because familial segregation has not been assessed.
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 in which missense variants are a common mechanism of disease." The evidence for this variant shows: missense impact unknown and gene constraint data unavailable. Therefore, this criterion is not applied because gene-specific missense constraints cannot be evaluated.
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." The evidence for this variant shows: CADD=0.36 (benign) and SpliceAI=0.23 (below significance threshold). Therefore, this criterion is not applied because in silico predictions do not support pathogenicity.
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 clinical context provided. Therefore, this criterion is not applied because phenotype 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." The evidence for this variant shows: ClinVar reports VUS, not pathogenic. Therefore, this criterion is not applied because no reputable source asserts pathogenicity.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in general population databases." The evidence for this variant shows: MAF=0.00279%, well below 5%. Therefore, this criterion is not applied because allele frequency is too low.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder." The evidence for this variant shows: MAF is below thresholds for DDX41-related disease. Therefore, this criterion is not applied because frequency does not exceed expected.
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 disorder with full penetrance expected at an early age." The evidence for this variant shows: no healthy adult genotype data with phenotype. Therefore, this criterion is not applied due to lack of data.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function." The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied because no evidence of benign function is available.
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 analysis. Therefore, this criterion is not applied because segregation data are missing.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants are known to cause disease." The evidence for this variant shows: variant type and effect unknown; DDX41 disease mechanism includes both missense and truncating variants. 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 dominant disorder, or observed in cis with a pathogenic variant for any disorder." The evidence for this variant shows: no phase or cis/trans information. 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: not an in-frame indel. Therefore, this criterion is not applied.
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 give low/benign scores but not uniformly no impact. Therefore, this criterion is not applied because computational evidence is mixed and below thresholds.
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 basis 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." The evidence for this variant shows: no reputable source reports benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact." The evidence for this variant shows: it is intronic and not synonymous coding. Therefore, this criterion is not applied.