About FGF3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGF3 c.351del, p.(Phe117LeufsTer41)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Moderate
PVS1 · moderate
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.
PM2Moderate
PM2 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 moderate, PM2 moderate; combination = 2 moderate, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 16 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 2
PVS1 ModerateNM_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. Details ▾Hide ▴
Evidence considered
- Frameshift variant in last exon (3/3) of FGF3
- predicted to escape NMD under PMC6185798
- p.(Phe117LeufsTer41) removes ~83 C-terminal amino acids (35% of protein) and replaces with 41 aberrant residues
- FGF3 loss of function supported as germline disease mechanism (candidate gene for branchio-oto-renal syndrome per PMID:23851940)
- No CSPEC/VCEP framework available
- generic PVS1 fallback applied
Still missing
- Specific functional characterization of the FGF3 C-terminal domain (aa 158-240) is not available in the case evidence
- FGF3 is a candidate gene for BOR syndrome
- not a definitively established disease gene — expert review of gene-disease validity is warranted
- NM_005247.2 is not MANE Select
- a more recent transcript version (NM_005247.4) is available
Sources
PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles observed)
- Absent from gnomAD v4.1 (0 alleles observed)
- Absent from gnomAD-Canada v1.0 (0 alleles observed)
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo data are available for this variant. No parental testing, trio sequencing, or family studies were identified in the evidence sources reviewed. Details ▾Hide ▴
Evidence considered
- No de novo observations found in ClinVar
- literature
- or other evidence sources
Still missing
- Parental testing data not available
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB lists oncogenicity as 'Unknown Oncogenic Effect' with no variant-specific functional data
- No functional studies identified in literature search
Still missing
- No experimental functional characterization of FGF3 p.(Phe117LeufsTer41) exists in the reviewed evidence
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar with zero submissions
- Variant absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
Still missing
- No patient observations available to assess prevalence in affected populations
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: no significant hotspot at FGF3 F117
- No curated functional domain evidence for the FGF3 C-terminus in the case materials
Still missing
- Functional domain annotation for FGF3 C-terminal region not available
PM6 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. Details ▾Hide ▴
Evidence considered
- No de novo observations in any evidence source
Still missing
- No trio or family-based testing data available
PP1 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. Details ▾Hide ▴
Evidence considered
- No family studies or cosegregation data identified
Still missing
- No family-based or pedigree data available
PP4 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. Details ▾Hide ▴
Evidence considered
- No patient phenotype
- clinical history
- or family history provided
Still missing
- Patient clinical data not included in case materials
PP5 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. Details ▾Hide ▴
BA1 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. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.00% across all gnomAD populations
- well below the 1% BA1 threshold
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.00% across all gnomAD populations
- well below the 0.3% BS1 threshold
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- No observations in any population database or clinical cohort
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- No functional studies identified for FGF3 p.(Phe117LeufsTer41)
Still missing
- No experimental functional data available for this variant
BS4 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. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available
Still missing
- No family or pedigree data
BP2 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. Details ▾Hide ▴
Evidence considered
- No observations in trans or in cis with any other variant
BP5 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. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular diagnosis identified
Still missing
- No clinical case data available
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. BP6 is not met. Details ▾Hide ▴
Evidence considered
- Variant not present in ClinVar
- no benign classifications from any source
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 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. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 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. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting: unable to parse missense residue context
- eligible_for_classic_pm5_search is false
- No same-residue comparator variants identified in ClinVar
Sources
pm5_candidates
PP2 N/APP2 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. Details ▾Hide ▴
No further detail was recorded.
PP3 N/APP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no predicted splice effect)
- REVEL and BayesDel not applicable to deletion variants
Sources
BP1 N/ABP1 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. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 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. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 indicates no cryptic splice alteration
- which is irrelevant to the frameshift's truncation mechanism
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 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. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- FGF3
- Transcript
- NM_005247.2
- Coding (HGVS c.)
- NM_005247.2:c.351del
- Protein (HGVS p.)
- NP_005238.1:p.(Phe117LeufsTer41)
- GRCh38
- chr11:69810673 CA>C
- GRCh37
- chr11:69625441 CA>C
Gene diagram
Every interpreted variant in FGF3, mapped onto the exon structure of NM_005247.2. Select a row to find it on the plot.
FGF3NM_005247.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FGF3
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no predicted splice effect)
- REVEL and BayesDel not applicable to deletion variants
Sources
BP4 N/ABP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 indicates no cryptic splice alteration
- which is irrelevant to the frameshift's truncation mechanism
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005247.2%3Ac.351del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-69625441-CA-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-69810673-CA-C?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-69810673-CA-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005247.2%3Ac.351d…
- OncoKB ↗www.oncokb.org/gene/FGF3/F117Lfs*41
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGF3+c.351del
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.