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
FBXO31
Final classification
Likely Pathogenic
FBXO31 c.1000G>A · p.Asp334Asn
FBXO31
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
Gene diagram
· NM_024735.5 · variants mapped to exon structure
FBXO31
NM_024735.5
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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
→PM6 supports · met
→PS3 supports · met
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 supports · met
Sources & reference links