About FGFR4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR4 c.317C>T, p.(Ser106Phe)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
NM_213647.2:c.317C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency < 0.1%), meeting the PM2 criterion for a variant absent or at extremely low frequency in large population cohorts.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of in silico evidence suggest no significant impact on gene product. BayesDel score is -0.025 (benign range), SpliceAI max delta is 0.00 (no predicted splice alteration), and REVEL score is 0.43 (below accepted pathogenicity thresholds). Together these predictors favor a neutral or minimally disruptive effect.
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: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, 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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR4, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification at low frequencies in various cancer types.
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 · 5 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_213647.2:c.317C>T (p.Ser106Phe) is absent from all queried population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at moderate strength.
Multiple in silico predictors suggest no significant impact on the gene product: BayesDel score is -0.025 (benign range), SpliceAI max delta is 0.00, and REVEL score of 0.43 falls below standard pathogenicity thresholds, meeting BP4 at supporting benign strength.
The variant is absent from ClinVar and the literature; no functional, segregation, de novo, case-control, or clinical classification data are available to assess PS1–PS5, PM6, PP1–PP5, BS2–BS4, BP2, BP5, or BP6.
PVS1 is not applicable: c.317C>T is a missense variant encoding p.Ser106Phe and does not fall into any null-variant bucket under the ClinGen SVI PVS1 decision tree (PMC6185798).
PM1 is not met: residue 106 is not a statistically significant mutational hotspot and FGFR4 lacks a germline disease-associated hotspot map.
PM5 is not applicable: no same-residue pathogenic comparator variant at codon 106 with a different amino acid change was identified in ClinVar.
BP1 is not met: while FGFR4 loss-of-function is supported as a disease mechanism by gene-level literature, the gene-disease validity has not been established at a ClinGen level and missense variants are not excluded as a disease mechanism.
The evidence profile consists of one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), resulting in conflicting evidence. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 ModerateNM_213647.2:c.317C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency < 0.1%), meeting the PM2 criterion for a variant absent or at extremely low frequency in large population cohorts. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada: absent (AC=0
- AF=0.0)
Sources
BP4 SupportingMultiple lines of in silico evidence suggest no significant impact on gene product. BayesDel score is -0.025 (benign range), SpliceAI max delta is 0.00 (no predicted splice alteration), and REVEL score is 0.43 (below accepted pathogenicity thresholds). Together these predictors favor a neutral or minimally disruptive effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.43 (below typical pathogenic threshold)
- BayesDel: -0.025 (benign-leaning)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
Not met · 5 · evaluated, threshold not reached
PM1 NM_213647.2:c.317C>T (p.Ser106Phe) is located in the extracellular immunoglobulin-like domain of FGFR4, but does not lie in a statistically significant mutational hotspot per cancerhotspots.org, and no germline disease-associated mutational hotspot encompassing codon 106 has been established for FGFR4. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: no significant hotspot at residue 106
- variant not in a well-established FGFR4 germline disease mutational hotspot
Still missing
- FGFR4 lacks a ClinGen-defined germline disease hotspot map
PP3 In silico predictors do not provide multiple lines of evidence supporting a deleterious effect. REVEL score is 0.43 (below typical pathogenicity threshold of 0.5), BayesDel is -0.025 (benign-leaning), and SpliceAI max delta is 0.00 (no predicted splice impact). These results do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.43 (indeterminate)
- BayesDel: -0.025 (benign-leaning)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BA1 NM_213647.2:c.317C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada: absent
Sources
BS1 NM_213647.2:c.317C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada: absent
Sources
BP1 Although FGFR4 loss-of-function is supported as a disease mechanism by targeted literature review (PMID:26186299, PMID:29735309, PMID:36973520, PMID:19863427, PMID:23880303), there is insufficient evidence that FGFR4-associated disease is caused exclusively by truncating variants such that BP1 would apply to a missense variant. The gene-disease validity has not been established at a ClinGen level. Details ▾Hide ▴
Evidence considered
- FGFR4 LOF mechanism supported by literature but gene-disease validity not at ClinGen level
- missense variants not excluded as disease mechanism
Still missing
- No ClinGen gene-disease validity curation for FGFR4
- unclear whether only truncating variants cause disease
Sources
pvs1_gene_context
Not assessed · 16 · no assessment recorded
PS1 No alternate nucleotide change producing the same amino acid substitution (p.Ser106Phe) has been identified as pathogenic in ClinVar or the literature. Without a known pathogenic comparator arising from a different nucleotide change at the same codon, PS1 cannot be assessed. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for this variant
- no same-residue pathogenic variants identified
Still missing
- No known pathogenic variant at codon 106 arising from a different nucleotide change
PS2 No de novo observation for NM_213647.2:c.317C>T was identified. Neither ClinVar submissions nor the literature report a confirmed de novo occurrence with parental testing. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature
Still missing
- No proband or parental testing data available
PS3 No well-established in vitro or in vivo functional studies were identified for NM_213647.2:c.317C>T (p.Ser106Phe). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. COSMIC has no entries for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data
- COSMIC: no entries
- no functional studies in literature
Still missing
- No functional assay data available for p.Ser106Phe
PS4 No case-control or statistical enrichment data are available for NM_213647.2:c.317C>T. The variant is absent from ClinVar and the literature, precluding any assessment of prevalence in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar and literature — no case-control data
Still missing
- No affected-vs-control prevalence data
PM6 No de novo observation with confirmed maternity and paternity was identified for NM_213647.2:c.317C>T. Neither ClinVar nor the literature report a de novo occurrence meeting PM6 requirements. Details ▾Hide ▴
Evidence considered
- No confirmed de novo reports with parental testing
Still missing
- No de novo data with confirmed parentage
PP1 No co-segregation data are available for NM_213647.2:c.317C>T. No family studies linking this variant to disease have been reported. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar or literature
Still missing
- No family-based co-segregation analysis
PP2 HCI prior scores are unavailable for FGFR4, and no gene-level missense constraint metric (e.g., missense Z-score) is available from the evidence pipeline. FGFR4 has not been established as a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- no missense Z-score or constraint data available for FGFR4
Still missing
- No FGFR4 missense constraint data
- gene-disease validity for germline missense mechanism not firmly established
PP4 No proband phenotype or clinical data are available for NM_213647.2:c.317C>T. The variant is novel with no associated clinical submissions in ClinVar. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data in ClinVar or literature
Still missing
- No proband clinical data for phenotype-specificity assessment
PP5 NM_213647.2:c.317C>T is absent from ClinVar and has not been classified by any reputable clinical laboratory or expert panel. No source credibly reports this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries
- no expert panel or clinical laboratory classification
Still missing
- No external classification from a reputable source
BS2 No data are available regarding observation of NM_213647.2:c.317C>T in healthy adults. The variant is absent from population databases, so BS2 (observed in a healthy adult for a fully penetrant disorder) cannot be evaluated without individual-level data. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no individual-level healthy-adult observation data
Still missing
- No individual-level data on healthy adult carriers
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of NM_213647.2:c.317C>T (p.Ser106Phe) were identified. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies in literature
Still missing
- No functional data demonstrating a benign effect
BS4 No segregation data are available to evaluate lack of segregation with disease. No family studies for NM_213647.2:c.317C>T have been reported. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family-based non-segregation data
BP2 No data are available regarding observation of NM_213647.2:c.317C>T in trans with a pathogenic dominant variant. The variant is absent from ClinVar and literature, precluding assessment of allelic configuration. Details ▾Hide ▴
Evidence considered
- No trans-configuration data available
Still missing
- No data on co-occurrence with a pathogenic variant in trans
BP5 No data are available regarding observation of NM_213647.2:c.317C>T in a case with an alternative molecular cause for disease. The variant is absent from ClinVar and literature. Details ▾Hide ▴
Evidence considered
- No data on co-occurrence with an alternate molecular cause
Still missing
- No data on cases with an alternative molecular basis
BP6 NM_213647.2:c.317C>T is absent from ClinVar and has not been classified as benign by any reputable source. No BP6 assessment is possible. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries
- no reputable source classifies this variant as benign
Still missing
- No benign classification from a reputable source
PS5 No familial segregation data are available for NM_213647.2:c.317C>T. No pedigrees or segregation analyses have been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar or literature
Still missing
- No family studies or segregation data
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_213647.2:c.317C>T is a missense variant (p.Ser106Phe) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- protein change NP_998812.1:p.(Ser106Phe)
- variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/AFGFR4 germline disease association and inheritance pattern are not established at a ClinGen level. PM3 (detected in trans with a pathogenic variant for recessive disorders) cannot be applied without a confirmed recessive inheritance model. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANM_213647.2:c.317C>T is a missense substitution, not an in-frame deletion or insertion. PM4 is reserved for protein length changes due to in-frame indels or stop-loss variants. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variant at codon 106 with a different amino acid change and a pathogenic classification was identified in ClinVar. The automatic PM5 candidate search found zero candidate variants at this residue. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- no pathogenic comparator at p.Ser106
Sources
pm5_candidates
BP3 N/ANM_213647.2:c.317C>T is a single-nucleotide substitution, not an in-frame deletion or insertion. BP3 is reserved for in-frame indels in repetitive regions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_213647.2:c.317C>T is a missense variant (p.Ser106Phe), not a synonymous or intronic variant. BP7 applies only to synonymous variants for which splicing prediction algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- BP7 reserved for synonymous variants
Identifiers
- Gene
- FGFR4
- Transcript
- NM_213647.2
- Coding (HGVS c.)
- NM_213647.2:c.317C>T
- Protein (HGVS p.)
- NP_998812.1:p.(Ser106Phe)
- GRCh38
- chr5:177090615 C>T
- GRCh37
- chr5:176517616 C>T
Gene diagram
Every interpreted variant in FGFR4, mapped onto the exon structure of NM_213647.2. Select a row to find it on the plot.
FGFR4NM_213647.2
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 FGFR4
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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
- 0.430
- BayesDel
- -0.025
How the predictions were used
BP4 SupportingMultiple lines of in silico evidence suggest no significant impact on gene product. BayesDel score is -0.025 (benign range), SpliceAI max delta is 0.00 (no predicted splice alteration), and REVEL score is 0.43 (below accepted pathogenicity thresholds). Together these predictors favor a neutral or minimally disruptive effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.43 (below typical pathogenic threshold)
- BayesDel: -0.025 (benign-leaning)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
PP3 In silico predictors do not provide multiple lines of evidence supporting a deleterious effect. REVEL score is 0.43 (below typical pathogenicity threshold of 0.5), BayesDel is -0.025 (benign-leaning), and SpliceAI max delta is 0.00 (no predicted splice impact). These results do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.43 (indeterminate)
- BayesDel: -0.025 (benign-leaning)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP7 N/ANM_213647.2:c.317C>T is a missense variant (p.Ser106Phe), not a synonymous or intronic variant. BP7 applies only to synonymous variants for which splicing prediction algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- BP7 reserved for synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.43. BayesDel score = -0.0252428.
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_213647.2%3Ac.317C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-176517616-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-177090615-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-177090615-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_213647.2%3Ac.317C…
- OncoKB ↗www.oncokb.org/gene/FGFR4/S106F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGFR4+c.317C%3ET
- 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). REVEL score = 0.43. BayesDel score = -0.0252428.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR4, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification at low frequencies in various cancer types.
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.