The FBXO31 c.1000G>A (p.Asp334Asn) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and is below the 0.1% threshold used here to support rarity.2 In a published functional study, fibroblast assays from affected individuals showed reduced cyclin D abundance relative to controls, and the authors interpreted p.Asp334Asn as causing increased cyclin D degradation, supporting a damaging effect on FBXO31 function.3 Published reports describe recurrent de novo occurrence in three unrelated affected individuals, while computational evidence is mixed: SpliceAI predicts no splice effect with a max delta score of 0.00, REVEL is 0.455, and BayesDel is -0.150532, so in silico data alone do not strongly support either PP3 or BP4.4
Final classification
Likely Pathogenic
PS3PM2PM6
FBXO31
c.1000G>A
p.Asp334Asn
This variant
The FBXO31 c.1000G>A (p.Asp334Asn) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM2 supporting, PM6 moderate; combination = 1 strong + 1 moderate + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PS3PM2PM6
Likely Pathogenic
FBXO31 c.1000G>A
PS3 + PM2 + PM6
→
Likely Pathogenic
4
PMID:32989326 ↗PMID:33675180 ↗spliceai ↗revelbayesdel
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.
Gene diagram
· NM_024735.5 · variants mapped to exon structure
FBXO31
NM_024735.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
In a published functional study, fibroblast assays from affected individuals showed reduced cyclin D abundance compared with controls, and the authors interpreted p.Asp334Asn as causing increased cyclin D degradation. This result supports a damaging functional effect for the variant.
Patient fibroblast cyclin D abundance assayVariant-specific functional interpretation consistent with damaging effect
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Its observed population frequency is therefore 0, which is below the 0.1% threshold used here to support rarity.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PM6
moderate
review
Pathogenic
This variant has been reported as de novo in three unrelated affected individuals across two publications. Because formal maternity and paternity confirmation was not documented in the retrieved evidence, these observations support PM6 rather than PS2.
Two de novo affected individuals reported in 2020One additional de novo affected individual reported in 2021
Assessed · not applied
· 10 not met · 7 not assessed
Pathogenic
PS1
No evidence was identified showing that a different nucleotide change producing the same amino acid substitution has already been established as pathogenic.
PS2
This variant has been reported as de novo in affected individuals, but the retrieved evidence did not document formal maternity and paternity confirmation.
PS4
This variant has been reported in multiple affected individuals, but no formal case-control enrichment analysis or other quantitative evidence was identified to show that its prevalence is significantly increased in affected individuals compared with controls.
PM1
Asp334 lies in a cyclin D interaction region of FBXO31, but available evidence does not show that this residue or region is a well-established mutational hotspot or a critical domain without benign variation.
PM5
No evidence was identified showing that a different missense change at codon 334 has already been established as pathogenic.
PP1
No segregation data were identified showing that this variant cosegregates with disease in affected relatives.
PP2
Available evidence was not sufficient to determine whether FBXO31 is a gene in which pathogenic missense variation is a common disease mechanism and benign missense variation is uncommon.
PP3
Computational evidence is mixed and does not strongly support a damaging effect.
PP4
Published affected individuals had a recurrent neurodevelopmental phenotype with prominent motor dysfunction, but the phenotype specificity for applying PP4 to this individual case was not established from the available evidence.
Benign
BA1
This variant is absent from gnomAD v2.1 and v4.1, so its population frequency is well below the 1% threshold for BA1.
BS1
This variant is absent from gnomAD v2.1 and v4.1, so its population frequency is below the 0.3% threshold used here for BS1 and does not support a benign interpretation.
BS2
No evidence was identified showing this variant in healthy adult individuals for a disorder with expected full penetrance at an early age.
BS3
No published functional study was identified showing normal or benign FBXO31 function for this variant.
BS4
No evidence was identified showing lack of segregation with disease or unaffected carriers in informative families.
BP2
No evidence was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant.
BP4
Computational evidence does not consistently support a benign effect.
BP5
No alternate molecular cause was identified that would explain the reported disease phenotype independently of this variant.
N/A · 8
PVS1 · PM3 · PM4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = -0.150532.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
→PM6
moderate
Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic c
Found
Structured finding pending for this record — see source link.
Applied to
→PM6
moderate
Sources & reference links