Variant classification summary

NM_005247.2:c.351del

FGF3 · NP_005238.1:p.(Phe117LeufsTer41) · NM_005247.2

GRCh37: chr11:69625441 CA>C · GRCh38: chr11:69810673 CA>C

Gene: FGF3 Transcript: NM_005247.2

Final call

VUS

PVS1 moderate PM2 moderate

Variant details

Gene

FGF3

Transcript

NM_005247.2

Protein

NP_005238.1:p.(Phe117LeufsTer41)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_005247.2:c.351del is a frameshift variant in exon 3 of 3 of FGF3 predicted to produce a truncated protein p.(Phe117LeufsTer41) with loss of the C-terminal 83 amino acids. PVS1 is applied at moderate strength under the ClinGen SVI framework (PMC6185798), downgraded from full strength due to location in the last exon with predicted NMD escape.

2

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.00%), meeting PM2 at moderate strength.

3

The variant is absent from ClinVar and has not been reported in the literature or somatic cancer databases (COSMIC). No functional studies, de novo observations, case-control data, or cosegregation evidence are available.

4

With two moderate pathogenic criteria (PVS1_Moderate, PM2_Moderate) and no benign criteria met, the evidence does not reach the threshold for Likely Pathogenic under generic ACMG/AMP 2015 rules (requires three moderate or two moderate plus two supporting criteria). This variant is classified as a Variant of Uncertain Significance (VUS). Additional evidence from functional studies, clinical observations, or family segregation data would be required to reclassify this variant.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Met	NM_005247.2:c.351del is a frameshift variant in exon 3 of 3 (the last exon) predicted to result in a truncated protein p.(Phe117LeufsTer41) with loss of approximately 35% of the C-terminal protein sequence and addition of 41 aberrant amino acids. FGF3 loss of function is supported as a germline disease mechanism (BOR syndrome candidate gene; PMID:23851940). Under ClinGen SVI PVS1 recommendations (PMC6185798), frameshift variants in the last exon are predicted to escape nonsense-mediated decay, which warrants a strength downgrade. The removed C-terminal region is substantial but its specific functional criticality has not been characterized in the evidence reviewed. PVS1 is applied at moderate strength given the established gene-level LoF mechanism tempered by NMD escape and uncertain functional domain characterization of the truncated region.	pvs1_generic_framework gnomad_v2 gnomad_v4
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant. This is a frameshift deletion (c.351del) that produces a novel C-terminal sequence, not a single nucleotide substitution, and cannot share the same amino acid change as any other variant.
PS2	Not met	No de novo data are available for this variant. No parental testing, trio sequencing, or family studies were identified in the evidence sources reviewed.
PS3	Not met	No functional studies testing this exact variant or a systematically characterized range that includes position 117 were identified. REVEL and BayesDel scores are not available for this non-SNV variant. The OncoKB entry for F117Lfs*41 lists 'Unknown Oncogenic Effect' and does not provide variant-specific functional evidence.	oncokb
PS4	Not met	The variant is absent from ClinVar and population databases. No case-control studies or patient cohorts with this variant were identified. There is no evidence of enrichment in affected individuals versus controls.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 requires a different nucleotide change at the same position as an established pathogenic missense variant. This is a single-nucleotide deletion (c.351del) producing a frameshift, not a missense substitution, and PS5 semantics do not apply.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org, and no specific functional domain characterization data for the FGF3 C-terminal region at position 117 is available in the case evidence to support a PM1 application at domain level.
PM2	Met	This variant is completely absent from all population databases (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), with an observed allele frequency of 0.00%. Under the generic ACMG/AMP framework, absence from large population cohorts at a frequency below 0.1% satisfies PM2 at moderate strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per adjudication instructions.
PM4	N/A	PM4 applies to non-frameshift protein length changes (in-frame deletions/insertions, stop-loss variants). This is a frameshift deletion; the null variant mechanism is captured under PVS1. PM4 should not be applied to frameshift variants.
PM5	N/A	PM5 requires a same-residue missense comparator classified as pathogenic. This frameshift deletion cannot be parsed into missense residue context, and automatic PM5 candidate harvesting determined PM5 semantics cannot be safely confirmed. No comparator variants at the same residue with a different amino acid change exist.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires a confirmed de novo event with maternity and paternity testing; no such data were identified in ClinVar, the literature, or other evidence sources.
PP1	Not met	No cosegregation data are available for this variant. PP1 requires demonstration of variant cosegregation with disease in multiple affected family members, which has not been reported in any evidence source.
PP2	N/A	PP2 is specific to missense variants in genes where missense variation is a common disease mechanism and benign missense variation is rare. This is a frameshift variant, not a missense change, and PP2 does not apply.
PP3	N/A	PP3 applies to missense or splice variants where multiple lines of computational evidence support a deleterious effect. For this frameshift variant, the pathogenic mechanism is protein truncation, which is already evaluated under PVS1. SpliceAI predicts no splice alteration (max delta 0.00), and REVEL/BayesDel are not applicable to non-SNV variants. Computational predictors for frameshift effects are not validated for PP3 application.	spliceai
PP4	Not met	No patient phenotype or clinical data are available in the case evidence. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology, which cannot be assessed without clinical context.
PP5	Not met	This variant is absent from ClinVar. No reputable source, expert panel, or clinical laboratory has classified this variant as pathogenic. PP5 requires a reputable source to have independently classified the variant as pathogenic.	clinvar
BA1	Not met	BA1 requires an allele frequency greater than 1% in population databases. This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.00%). The BA1 threshold is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires an allele frequency greater than 0.3% in population databases for non-VCEP assessment. This variant is completely absent from gnomAD (allele frequency 0.00%), falling well below the BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual (for fully penetrant disorders) or in trans with a pathogenic variant (for recessive disorders). This variant has not been observed in any individual, healthy or affected, in the available evidence.	gnomad_v2 gnomad_v4
BS3	Not met	BS3 requires well-established functional studies demonstrating no deleterious effect. No functional studies of any kind were identified for this variant in the evidence sources reviewed.
BS4	Not met	BS4 requires lack of segregation with disease in affected family members. No family-based cosegregation or non-segregation data are available for this variant in any evidence source.
BP1	N/A	BP1 is specific to missense variants in genes where truncating variants are the primary disease mechanism. This is a frameshift truncating variant, not a missense change, and BP1 does not apply.
BP2	Not met	BP2 requires observation in trans with a pathogenic variant in a gene associated with a recessive disorder, or in cis with a pathogenic variant in a dominant disorder. No such observations have been reported for this variant.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This is a frameshift deletion, not an in-frame change, and BP3 does not apply.
BP4	N/A	BP4 is intended for missense and splice variants where multiple computational lines of evidence suggest no impact on gene product. For this frameshift variant, the pathogenic mechanism is protein truncation (evaluated under PVS1), not splicing alteration. SpliceAI's prediction of no splice effect (max delta 0.00) does not speak to whether the frameshift itself is damaging and cannot be used to apply BP4. Using SpliceAI to dismiss a frameshift's pathogenicity would be an incorrect application of BP4.	spliceai
BP5	Not met	BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such clinical cases have been reported in the evidence reviewed.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. BP6 is not met.	clinvar
BP7	N/A	BP7 applies to synonymous variants where the nucleotide change does not alter the amino acid sequence and splicing predictors show no impact. This is a frameshift deletion that profoundly alters the protein sequence; BP7 does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.