About FGFR4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR4 c.1144G>T, p.(Val382Leu)
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 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), consistent with a rare variant meeting the PM2 allele frequency threshold of <0.1% in population databases.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest this variant has no deleterious impact: REVEL score 0.056 (strongly benign, well below 0.5), BayesDel score -0.280588 (benign), and SpliceAI max delta 0.00 (no predicted splicing alteration). Three independent in silico tools consistently predict 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 benign; 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 · 9 not met · 0 not assessed · 18 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): Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant meeting the PM2 allele frequency threshold of <0.1%.
BP4 (supporting benign): Multiple lines of computational evidence predict a benign effect — REVEL 0.056, BayesDel -0.280588, and SpliceAI max delta 0.00.
PVS1, PS1-PS5, PM1, PM5-PM6, PP1-PP5, BA1, BS1-BS4, BP1-BP2, BP5-BP7 are not met or not applicable for this missense variant lacking variant-specific clinical, functional, or literature evidence.
Conflicting criteria (PM2 supporting pathogenic vs. BP4 supporting benign) result in a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 classification framework.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), consistent with a rare variant meeting the PM2 allele frequency threshold of <0.1% in population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0.0)
- gnomAD v4.1: absent (AF = 0.0)
- gnomAD-Canada v1.0: absent (AF = 0.0)
Sources
BP4 SupportingMultiple lines of computational evidence suggest this variant has no deleterious impact: REVEL score 0.056 (strongly benign, well below 0.5), BayesDel score -0.280588 (benign), and SpliceAI max delta 0.00 (no predicted splicing alteration). Three independent in silico tools consistently predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.056 (benign
- threshold ≥0.5 for damaging)
- BayesDel: -0.280588 (benign
- negative scores support benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
Not met · 9 · evaluated, threshold not reached
PS3 No variant-specific functional studies were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and no experimental functional data for p.Val382Leu was found in the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect — no variant-specific reviewed functional evidence
- No PMIDs with functional data for this variant identified in literature_pass
Still missing
- No functional studies of p.Val382Leu in FGFR4 are available
Sources
PM1 Position 382 is not in a statistically significant cancer hotspot (cancerhotspots.org negative). Although FGFR4 contains well-characterized functional domains including an intracellular tyrosine kinase domain, no literature evidence establishes residue 382 (located in the extracellular region) as lying within a critical functional domain where missense variants are an established disease mechanism. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not significant
- exact variant not listed
- Residue 382 lies in the FGFR4 extracellular region
- not in the tyrosine kinase domain
Still missing
- No functional domain characterization specific to residue 382
PP2 PP2 requires a gene with a low rate of benign missense variation and a high proportion of pathogenic missense variants. HCI prior data is not available for FGFR4, and no gnomAD constraint metrics (Z-score, pLI, missense o/e) have been provided to support a low benign missense tolerance for this gene. Details ▾Hide ▴
Evidence considered
- HCI Prior: gene FGFR4 not supported
- No constraint metrics (Z-score
- missense o/e) available in the case data
Still missing
- No gene-level constraint or benign missense tolerance data for FGFR4
PP3 Multiple in silico predictors support a benign effect: REVEL score 0.056 (strongly benign, well below 0.5 threshold), BayesDel score -0.280588 (negative/benign), and SpliceAI max delta 0.00 (no predicted splicing impact). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.056 (benign
- threshold ≥0.5 for damaging)
- BayesDel: -0.280588 (benign
- negative scores favor benign)
- SpliceAI: max delta 0.00 (no splicing impact predicted)
Sources
BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0.0%, well below the BA1 threshold of >1.0%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0.0
- BA1 threshold >1.0%)
- gnomAD v4.1: absent (AF = 0.0)
- gnomAD-Canada v1.0: absent (AF = 0.0)
Sources
BS1 This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0.0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0.0
- BS1 threshold >0.3%)
- gnomAD v4.1: absent (AF = 0.0)
- gnomAD-Canada v1.0: absent (AF = 0.0)
Sources
BS2 This variant is absent from gnomAD population databases and has not been observed in any healthy adult individual, homozygous or heterozygous. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no observation in healthy adults
Sources
BS3 No functional studies demonstrating a benign effect for p.Val382Leu have been identified. The absence of functional data does not constitute evidence of a benign effect. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional studies of p.Val382Leu available
Still missing
- No functional studies of this variant exist
BP1 FGFR4 is a receptor tyrosine kinase in the FGFR family. Established germline FGFR family disease mechanisms are predominantly gain-of-function missense mutations (e.g., FGFR2 in Apert syndrome, FGFR3 in achondroplasia), not primarily truncating variants. BP1 requires a gene where truncating variants are the primary disease mechanism, which is not the case for FGFR4. Details ▾Hide ▴
Evidence considered
- FGFR4 belongs to a receptor tyrosine kinase family where germline disease is predominantly driven by gain-of-function missense variants
- PMID:23880303: FGFR review describes somatic and germline FGFR mutations as gain-of-function
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Val382Leu); does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per PMC6185798. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (c.1144G>T
- p.Val382Leu)
- Variant bucket: 'other' — not a predicted null variant per ClinGen SVI PVS1 framework
Sources
PS1 N/ANo previously established pathogenic variant with the same amino acid change (p.Val382Leu) has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no comparator pathogenic variant with same amino acid change available
Sources
PS2 N/ANo de novo data or parental testing information is available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or de novo reports identified in the case data
Still missing
- No parental or trio testing data available
PS4 N/ANo case-control or cohort studies comparing variant prevalence in affected vs. unaffected individuals are available. Details ▾Hide ▴
Evidence considered
- No case-control or prevalence data identified
- variant absent from all population and clinical databases
Still missing
- No affected vs. control cohort data available
PM3 N/AVariant is absent from population databases and has not been observed in trans with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans configuration data available
PM4 N/AVariant is a missense substitution; PM4 applies only to non-repeat-region stop-loss, in-frame deletions/insertions, or single-amino-acid deletions. Details ▾Hide ▴
Evidence considered
- Variant is a single-nucleotide missense substitution
PM5 N/ANo other pathogenic missense variants at the same residue (p.Val382) were identified in ClinVar; PM5 candidate harvesting returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue pathogenic missense comparators at p.Val382
Sources
pm5_candidatesclinvar ↗
PM6 N/ANo de novo observation (with or without confirmed maternity/paternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in any data source
Still missing
- No trio or de novo testing data available
PP1 N/ANo family segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation or family studies identified
Still missing
- No family studies available
PP4 N/ANo patient phenotype information is available to assess whether the clinical presentation is specific for FGFR4-related disease. Details ▾Hide ▴
Evidence considered
- No phenotype data provided for the proband
Still missing
- No phenotype information available
PP5 N/AThis variant is absent from ClinVar; no reputable source has classified it as pathogenic. ClinVar absence precludes PP5 application at any strength. Details ▾Hide ▴
Evidence considered
- ClinVar: variant not present
- no classification from any submitter
Sources
BS4 N/ANo family segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
- No family data available
Still missing
- No segregation data available
BP2 N/ANo observation of this variant in trans with a known pathogenic variant is available. Details ▾Hide ▴
Evidence considered
- No phase data or trans observations available
Still missing
- No trans configuration data
BP3 N/AVariant is a missense substitution; BP3 applies only to in-frame insertions/deletions in non-repeat regions. Details ▾Hide ▴
Evidence considered
- Variant is a single-nucleotide missense substitution
- not an in-frame indel
BP5 N/ANo alternate molecular basis for disease has been identified in this case. Details ▾Hide ▴
Evidence considered
- No alternate genetic cause identified
Still missing
- No data on alternate genetic findings
BP6 N/AThis variant is absent from ClinVar; no reputable source has classified it as benign. ClinVar absence precludes BP6 application. Details ▾Hide ▴
Evidence considered
- ClinVar: variant not present
- no classification from any submitter
Sources
BP7 N/Ac.1144G>T is a missense variant (p.Val382Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact, or intronic variants outside conserved splice sites. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Val382Leu)
- BP7 is restricted to synonymous/intronic variants
PS5 N/AThis variant is absent from ClinVar and has no classification from a reputable source. Details ▾Hide ▴
Evidence considered
- ClinVar: variant not present
- no classification from any submitter
Sources
Identifiers
- Gene
- FGFR4
- Transcript
- NM_213647.2
- Coding (HGVS c.)
- NM_213647.2:c.1144G>T
- Protein (HGVS p.)
- NP_998812.1:p.(Val382Leu)
- GRCh38
- chr5:177093224 G>T
- GRCh37
- chr5:176520225 G>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
- 0.056
- BayesDel
- -0.281
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest this variant has no deleterious impact: REVEL score 0.056 (strongly benign, well below 0.5), BayesDel score -0.280588 (benign), and SpliceAI max delta 0.00 (no predicted splicing alteration). Three independent in silico tools consistently predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.056 (benign
- threshold ≥0.5 for damaging)
- BayesDel: -0.280588 (benign
- negative scores support benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
PP3 Multiple in silico predictors support a benign effect: REVEL score 0.056 (strongly benign, well below 0.5 threshold), BayesDel score -0.280588 (negative/benign), and SpliceAI max delta 0.00 (no predicted splicing impact). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.056 (benign
- threshold ≥0.5 for damaging)
- BayesDel: -0.280588 (benign
- negative scores favor benign)
- SpliceAI: max delta 0.00 (no splicing impact predicted)
Sources
BP7 N/Ac.1144G>T is a missense variant (p.Val382Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact, or intronic variants outside conserved splice sites. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Val382Leu)
- BP7 is restricted to synonymous/intronic variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.056. BayesDel score = -0.280588.
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.1144G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-176520225-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-177093224-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-177093224-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_213647.2%3Ac.1144…
- OncoKB ↗www.oncokb.org/gene/FGFR4/V382L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGFR4+c.1144G%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 = 0.056. BayesDel score = -0.280588.
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.