About FGFR4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR4 c.25G>A, p.(Gly9Arg)
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
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of allele frequency <0.1% in large population databases for a gene without a CSPEC/VCEP population frequency framework.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.39 (below the pathogenic threshold of 0.5), BayesDel score is -0.119 (negative, in the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00). Multiple in silico predictors concordantly support a benign 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 supporting, BP4 supporting; combination = 1 supporting + 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 · 4 not met · 16 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM2 (supporting): This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.
BP4 (supporting): Multiple computational predictors — REVEL (0.39), BayesDel (-0.119), and SpliceAI (max delta 0.00) — concordantly suggest no deleterious impact on the gene product.
PVS1 is not applicable as this is a missense variant (p.Gly9Arg) and does not qualify as a null variant under the ClinGen SVI PVS1 framework.
No CSPEC/VCEP framework exists for FGFR4; classification follows generic ACMG/AMP 2015 combination rules (Richards et al. 2015, PMID:25741868).
Under generic ACMG/AMP 2015 rules, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) do not meet any classification threshold. This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of allele frequency <0.1% in large population databases for a gene without a CSPEC/VCEP population frequency framework. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.39 (below the pathogenic threshold of 0.5), BayesDel score is -0.119 (negative, in the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00). Multiple in silico predictors concordantly support a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.39 (below pathogenic threshold of 0.5).
- BayesDel: -0.119 (negative score
- consistent with benign).
- SpliceAI: max delta 0.00 (no predicted splice alteration).
Sources
Not met · 4 · evaluated, threshold not reached
PM1 This variant (p.Gly9Arg at residue 9) does not lie in a statistically significant mutational hotspot as assessed by CancerHotspots.org, nor is it located in a well-characterized critical functional domain with established pathogenic enrichment for FGFR4. Details ▾Hide ▴
Evidence considered
- CancerHotspots: residue not statistically significant
- variant not listed as hotspot.
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.39 (below the pathogenic threshold of 0.5, in the indeterminate range), BayesDel score is -0.119 (negative, supporting a benign prediction), and SpliceAI predicts no splicing impact (max delta score = 0.00). PP3 requires multiple computational predictors to concordantly support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.39 (indeterminate
- below pathogenic threshold).
- BayesDel: -0.119 (benign range).
- SpliceAI: max delta 0.00 (no predicted splice impact).
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency greater than 1% in any population. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- allele frequency is 0%.
Sources
BS1 This variant is absent from gnomAD across all populations. BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic ACMG). Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- allele frequency is 0%.
Sources
Not assessed · 16 · no assessment recorded
PS1 Insufficient evidence: no known pathogenic variant with the same amino acid change (p.Gly9Arg) has been identified in ClinVar or the literature. A comparator pathogenic variant at this residue is required for PS1. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no same-amino-acid pathogenic comparator identified.
Still missing
- No known pathogenic variant with the same amino acid change at Gly9.
Sources
PS2 No de novo data are available for this variant. PS2 requires confirmed de novo occurrence with both parental samples tested and maternity/paternity confirmed. Details ▾Hide ▴
Still missing
- No de novo confirmation data available.
PS3 No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no reviewed functional evidence. PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
Still missing
- No variant-specific functional assays available.
Sources
PS4 No case-control data are available to assess whether the variant has significantly increased prevalence in affected individuals versus controls. Details ▾Hide ▴
Still missing
- No case-control or cohort prevalence data available.
PM6 No de novo data are available. PM6 requires a de novo observation with maternity/paternity confirmed, with the variant being absent in both biological parents. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No cosegregation data are available. PP1 requires evidence of cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP2 HCI prior probability data are unavailable for FGFR4. PP2 requires a low rate of benign missense variation in the gene coupled with a high proportion of pathogenic missense variants, which cannot be assessed without HCI prior scores. Details ▾Hide ▴
Evidence considered
- HCI prior not found for FGFR4 — cannot assess gene-level missense constraint.
Still missing
- HCI prior data unavailable for FGFR4.
PP4 No phenotype or family history data specific to this variant are available. PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No phenotype or family history data available.
PP5 This variant has not been classified as pathogenic by any reputable clinical laboratory or expert panel. PP5 requires a prior pathogenic classification from a source whose evidence has not been independently reviewed. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no prior pathogenic classification.
Still missing
- No prior pathogenic classification available.
Sources
BS2 No data are available regarding observation of this variant in healthy adult individuals with complete ascertainment. BS2 requires the variant to be observed in a healthy adult individual for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No healthy control ascertainment data available.
BS3 No well-established functional studies demonstrating no deleterious effect were identified. BS3 requires functional assays that convincingly show the variant does not impair protein function. Details ▾Hide ▴
Still missing
- No functional studies demonstrating no deleterious effect available.
BS4 No segregation data are available to evaluate nonsegregation with disease. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No data are available regarding observation in trans with a pathogenic variant. BP2 requires the variant to be observed in trans with a pathogenic variant for a fully penetrant recessive disorder; the FGFR4 disease spectrum does not clearly follow a recessive inheritance pattern. Details ▾Hide ▴
Still missing
- No trans phasing data
- FGFR4 disease inheritance pattern is not well established as recessive.
BP5 No data are available regarding an alternative molecular cause for the phenotype. BP5 requires that the variant be found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Still missing
- No data on alternative molecular causes.
BP6 This variant has not been classified as benign by a reputable source. BP6 requires a prior benign classification from a reputable clinical laboratory or database. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no prior benign classification.
Still missing
- No prior benign classification available.
Sources
PS5 This variant has no ClinVar submissions and has not been reported as pathogenic by a reputable source with independent evidence. PS5 is reserved for variants recently described as pathogenic with evidence not yet independently verified. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no prior classification by a reputable source.
Still missing
- No prior pathogenic classification from a reputable source.
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_213647.2:c.25G>A is a missense variant (p.Gly9Arg) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants as defined by the ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant p.(Gly9Arg) is not a predicted null variant
- apply_generic_pvs1_framework is false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ASkipped per workflow instruction: not assessed for this case. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per workflow instruction: not assessed for this case. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo known pathogenic missense variant at the same residue (Gly9) with a different amino acid change was identified in ClinVar or the literature. PM5 requires a comparator pathogenic missense variant at the same codon. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found zero same-residue candidates
- no expert-panel pathogenic comparator at p.Gly9.
Sources
pm5_candidatesclinvar ↗
BP1 N/AFGFR4 disease mechanisms include gain-of-function missense variants (as a receptor tyrosine kinase implicated in cancer via mutation, amplification, and rearrangement). BP1 is intended for genes in which only truncating variants cause disease, which does not apply to FGFR4. Details ▾Hide ▴
Evidence considered
- FGFR4 is a receptor tyrosine kinase with gain-of-function missense variants implicated in disease
- BP1 is not applicable to genes where missense variants are a recognized disease mechanism.
BP3 N/ASkipped per workflow instruction: not assessed for this case. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_213647.2:c.25G>A is a missense variant (p.Gly9Arg), not a synonymous variant. BP7 only applies to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Gly9Arg)
- BP7 is restricted to synonymous variants.
Identifiers
- Gene
- FGFR4
- Transcript
- NM_213647.2
- Coding (HGVS c.)
- NM_213647.2:c.25G>A
- Protein (HGVS p.)
- NP_998812.1:p.(Gly9Arg)
- GRCh38
- chr5:177089627 G>A
- GRCh37
- chr5:176516628 G>A
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
- 0.390
- BayesDel
- -0.119
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.39 (below the pathogenic threshold of 0.5), BayesDel score is -0.119 (negative, in the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00). Multiple in silico predictors concordantly support a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.39 (below pathogenic threshold of 0.5).
- BayesDel: -0.119 (negative score
- consistent with benign).
- SpliceAI: max delta 0.00 (no predicted splice alteration).
Sources
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.39 (below the pathogenic threshold of 0.5, in the indeterminate range), BayesDel score is -0.119 (negative, supporting a benign prediction), and SpliceAI predicts no splicing impact (max delta score = 0.00). PP3 requires multiple computational predictors to concordantly support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.39 (indeterminate
- below pathogenic threshold).
- BayesDel: -0.119 (benign range).
- SpliceAI: max delta 0.00 (no predicted splice impact).
Sources
BP7 N/ANM_213647.2:c.25G>A is a missense variant (p.Gly9Arg), not a synonymous variant. BP7 only applies to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Gly9Arg)
- BP7 is restricted to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.39. BayesDel score = -0.119489.
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.25G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-176516628-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-177089627-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-177089627-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_213647.2%3Ac.25G%…
- OncoKB ↗www.oncokb.org/gene/FGFR4/G9R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGFR4+c.25G%3EA
- 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 = 0.39. BayesDel score = -0.119489.
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.