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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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