PM2 (supporting): This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.1 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.2 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.3 No CSPEC/VCEP framework exists for FGFR4; classification follows generic ACMG/AMP 2015 combination rules (Richards et al. 2015, PMID:25741868).4 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).5
FGFR4
Final classification
VUS
FGFR4 c.25G>A · p.Gly9Arg
FGFR4
PM2 (supporting): This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.
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.
Classification rationale
PM2
BP4
VUS
FGFR4 c.25G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
3
pvs1_variant_assessmentpvs1_generic_framework ↗
4
generic_acmg_combination_rules
5
generic_acmg_combination_rules
Gene diagram
· NM_213647.2 · variants mapped to exon structure
FGFR4
NM_213647.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (genomes).
✓
BP4
supporting
Benign
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.
REVEL: 0.39 (below pathogenic threshold of 0.5).BayesDel: -0.119 (negative scoreconsistent with benign).
Assessed · not applied
Pathogenic
PS1
Insufficient evidence: no known pathogenic variant with the same amino acid change (p.Gly9Arg) has been identified in ClinVar or the literature.
PS2
No de novo data are available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control data are available to assess whether the variant has significantly increased prevalence in affected individuals versus controls.
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.
PM6
No de novo data are available.
PP1
No cosegregation data are available.
PP2
HCI prior probability data are unavailable for FGFR4.
PP3
Multiple lines of in silico evidence do not support a deleterious effect.
PP4
No phenotype or family history data specific to this variant are available.
PP5
This variant has not been classified as pathogenic by any reputable clinical laboratory or expert panel.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from gnomAD across all populations.
BS2
No data are available regarding observation of this variant in healthy adult individuals with complete ascertainment.
BS3
No well-established functional studies demonstrating no deleterious effect were identified.
BS4
No segregation data are available to evaluate nonsegregation with disease.
BP2
No data are available regarding observation in trans with a pathogenic variant.
BP5
No data are available regarding an alternative molecular cause for the phenotype.
BP6
This variant has not been classified as benign by a reputable source.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links