NM_005247.2:c.623C>A (p.Pro208His) in FGF3 is a missense variant absent from gnomAD v4.1 (0/1,568,532 alleles) and gnomAD v2.1, meeting PM2 at supporting strength.1 Multiple in silico predictors uniformly suggest a benign impact: REVEL 0.214 (benign), BayesDel -0.393656 (benign), and SpliceAI delta 0.00 (no splicing impact), meeting BP4 at supporting strength.2 The variant is absent from ClinVar, with no pathogenic or benign assertions from any submitter. No functional studies, segregation data, or case-control evidence were identified in the literature.3 With PM2 (supporting pathogenic) and BP4 (supporting benign), the evidence is conflicting and insufficient to reach any classification threshold under the generic ACMG/AMP 2015 framework (PMID:25741868). This variant is classified as a Variant of Uncertain Significance (VUS).4
FGF3
Final classification
VUS
FGF3 c.623C>A · p.Pro208His
FGF3
NM_005247.2:c.623C>A (p.Pro208His) in FGF3 is a missense variant absent from gnomAD v4.1 (0/1,568,532 alleles) and gnomAD v2.1, meeting PM2 at supporting strength.
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
FGF3 c.623C>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_005247.2 · variants mapped to exon structure
FGF3
NM_005247.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,568,532 alleles, AF=0.0), with an upper 95% CI well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0. Complete population absence across large, diverse population databases supports PM2 at supporting level.
Absent from gnomAD v2.1 exomes.Absent from gnomAD v4.1 (0/1568
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.214 (benign range, below 0.5 threshold). BayesDel score is -0.393656 (benign, negative score). SpliceAI max delta is 0.00 (no predicted splice alteration). All three independent in silico predictors agree on a benign prediction, meeting BP4 at supporting level.
REVEL score 0.214 (benignbelow 0.5 threshold).BayesDel score -0.393656 (benign
Assessed · not applied
Pathogenic
PS1
No pathogenic missense variant has been reported at the same amino acid residue (Pro208) with a different nucleotide change.
PS2
No de novo occurrence data are available for this variant.
PS3
No variant-specific functional studies were identified in the literature.
PS4
No case-control or cohort data demonstrating significantly increased prevalence of this variant in affected individuals compared to controls.
PM1
This variant does not lie within a statistically significant mutational hotspot (cancerhotspots.org).
PM5
PM5 requires a pathogenic missense variant at the same amino acid residue with a different amino acid change.
PM6
No de novo occurrence data (with or without confirmed parentage) are available for this variant.
PP1
No co-segregation data in affected families are available for this variant.
PP2
Insufficient data to assess whether FGF3 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease.
PP3
Multiple in silico predictors suggest a benign impact.
PP4
No patient phenotype or family history data are available for this assessment.
PP5
This variant is absent from ClinVar.
Benign
BA1
This variant is absent from all gnomAD populations (global AF = 0.0 in v4.1; 0/1,568,532 alleles).
BS1
This variant is absent from all gnomAD populations (global AF = 0.0 in v4.1; 0/1,568,532 alleles).
BS2
Not observed in any homozygous state in gnomAD (homozygotes = 0 in v4.1 across 1,568,532 alleles).
BS3
No well-established functional studies demonstrating no damaging effect were identified for this variant.
BS4
No segregation data in affected families are available to demonstrate lack of segregation with disease.
BP1
Insufficient data to determine whether FGF3 disease is caused primarily by truncating variants rather than missense variants.
BP2
No data on observation of this variant in trans with a pathogenic variant (for a fully penetrant dominant disorder) or in cis with a pathogenic variant (any inheritance pattern).
BP5
No data on observation of this variant in a case with an alternate molecular basis for disease are available.
BP6
This variant is absent from ClinVar.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1568532 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74128 alleles, homozygotes = 0).
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 / 1,568,532
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 = 0.214. BayesDel score = -0.393656.
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. FGF3, a fibroblast growth factor, is altered by amplification 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 previously been reported in somatic cancers (COSMIC; COSV107388255, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links