NM_024735.5:c.1000G>A

FBXO31 · NP_079011.3:p.(Asp334Asn) · NM_024735.5

GRCh37: chr16:87367889 C>T · GRCh38: chr16:87334283 C>T

Gene: FBXO31 Transcript: NM_024735.5

Final call

Likely Pathogenic

PS3 strong PM2 supporting PM6 moderate

Variant details

Gene

FBXO31

Transcript

NM_024735.5

Protein

NP_079011.3:p.(Asp334Asn)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, and the generic PVS1 framework is not applicable because the variant does not create a nonsense, frameshift, or canonical ±1,2 splice change. Although gene-level review indicated that loss of function may be a disease mechanism for FBXO31, this specific variant does not meet the null-variant entry criteria for PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that a different nucleotide change producing the same amino acid substitution has already been established as pathogenic.	clinvar
PS2	Not met	This variant has been reported as de novo in affected individuals, but the retrieved evidence did not document formal maternity and paternity confirmation. The de novo observations therefore do not meet the full requirements for PS2.	PMID:32989326 PMID:33675180
PS3	Met	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.	PMID:32989326
PS4	Not met	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.	PMID:32989326 PMID:33675180 gnomad_v2 gnomad_v4
PM1	Not met	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. Cancer Hotspots also did not identify a statistically significant hotspot at this position.	PMID:32989326 hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	No evidence was identified for this variant in trans with a pathogenic variant in a recessive disease context, so PM3 is not applicable.	clinvar
PM4	N/A	This is not an in-frame deletion, in-frame insertion, or protein length change, so PM4 is not applicable.	clinvar
PM5	Not assessed	No evidence was identified showing that a different missense change at codon 334 has already been established as pathogenic.	clinvar
PM6	Met	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.	PMID:32989326 PMID:33675180
PP1	Not met	No segregation data were identified showing that this variant cosegregates with disease in affected relatives.	PMID:33675180 clinvar
PP2	Not assessed	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.	clinvar
PP3	Not met	Computational evidence is mixed and does not strongly support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.455, and BayesDel is -0.150532; these values do not provide strong pathogenic computational support.	spliceai revel bayesdel
PP4	Not assessed	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.	PMID:33675180 PMID:32989326
PP5	N/A	PP5 was not applied because assertion by an external source without independently reviewable evidence is not used here.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1, so its population frequency is well below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals for a disorder with expected full penetrance at an early age.	gnomad_v2 gnomad_v4
BS3	Not met	No published functional study was identified showing normal or benign FBXO31 function for this variant. Available functional evidence instead supports a damaging effect.	PMID:32989326
BS4	Not met	No evidence was identified showing lack of segregation with disease or unaffected carriers in informative families.	PMID:33675180 clinvar
BP1	N/A	BP1 was not applied because available evidence does not show that FBXO31 disease is caused primarily by truncating variants with missense variants generally benign.	PMID:32989326 PMID:33675180
BP2	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant.	clinvar
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable.	clinvar
BP4	Not met	Computational evidence does not consistently support a benign effect. Although SpliceAI predicts no splice impact with a max delta score of 0.00 and BayesDel is -0.150532, REVEL is 0.455, so the overall in silico evidence is not strong enough for BP4.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular cause was identified that would explain the reported disease phenotype independently of this variant.	PMID:33675180
BP6	N/A	BP6 was not applied because assertion by an external source without independently reviewable evidence is not used here.	clinvar
BP7	N/A	This criterion is not applicable because the variant is missense rather than synonymous or deep intronic.	clinvar

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