NM_005247.2:c.623C>A

FGF3 · NP_005238.1:p.(Pro208His) · NM_005247.2

GRCh37: chr11:69625170 G>T · GRCh38: chr11:69810402 G>T

Gene: FGF3 Transcript: NM_005247.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FGF3

Transcript

NM_005247.2

Protein

NP_005238.1:p.(Pro208His)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is reserved for null variants (nonsense, frameshift, canonical splice ±1,2). This variant is a missense substitution (NP_005238.1:p.Pro208His) and falls into the 'other' bucket under the ClinGen SVI PVS1 decision tree (PMC6185798); it does not qualify for PVS1.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No pathogenic missense variant has been reported at the same amino acid residue (Pro208) with a different nucleotide change. The variant is absent from ClinVar.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant. No pedigree or trio sequencing data were identified.
PS3	Not met	No variant-specific functional studies were identified in the literature. OncoKB reports unknown oncogenic effect with no curated functional evidence. COSMIC records one somatic observation (COSV107388255, n=1) without accompanying functional data. No experimental studies have characterized this variant or a systematic range encompassing residue 208.	oncokb
PS4	Not met	No case-control or cohort data demonstrating significantly increased prevalence of this variant in affected individuals compared to controls. The variant is absent from ClinVar and no patient cohort studies were identified.
PS5	N/A	PS5 is not a criterion in the generic ACMG/AMP 2015 framework (PMID:25741868). No applicable standard exists for assessment under the current framework mode.	generic_acmg_combination_rules
PM1	Not met	This variant does not lie within a statistically significant mutational hotspot (cancerhotspots.org). No ClinVar pathogenic variants have been reported at the same residue (Pro208). No critical functional domain characterization specific to FGF3 residue 208 was identified in the available evidence.	clinvar
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	PM5 requires a pathogenic missense variant at the same amino acid residue with a different amino acid change. The automated PM5 candidate search found no same-residue comparator variants in ClinVar. No pathogenic variant at FGF3 codon 208 (Pro208) was identified.	pm5_candidates
PM6	Not met	No de novo occurrence data (with or without confirmed parentage) are available for this variant. No publications report de novo status for NM_005247.2:c.623C>A.
PP1	Not met	No co-segregation data in affected families are available for this variant.
PP2	Not met	Insufficient data to assess whether FGF3 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. No gnomAD missense constraint metrics (e.g., missense Z-score) or gene-level missense burden data were available for this assessment.
PP3	Not met	Multiple in silico predictors suggest a benign impact. REVEL score is 0.214 (benign range, below 0.5 threshold). BayesDel score is -0.393656 (negative, indicating benign). SpliceAI max delta score is 0.00 (no predicted splice impact). Computational evidence does not support a deleterious effect; collectively, predictors favor benign.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for this assessment. PP4 requires a phenotype highly specific for a disease with a single genetic etiology.
PP5	Not met	This variant is absent from ClinVar. No reputable source has reported this variant as pathogenic. No ClinVar 3-star expert panel classification exists.	clinvar
BA1	Not met	This variant is absent from all gnomAD populations (global AF = 0.0 in v4.1; 0/1,568,532 alleles). Does not exceed the 1% BA1 threshold.	gnomad_v4
BS1	Not met	This variant is absent from all gnomAD populations (global AF = 0.0 in v4.1; 0/1,568,532 alleles). Does not exceed the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	Not observed in any homozygous state in gnomAD (homozygotes = 0 in v4.1 across 1,568,532 alleles). No data on observation in trans with a pathogenic variant are available.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect were identified for this variant. No experimental data characterize the functional impact of p.Pro208His.	oncokb
BS4	Not met	No segregation data in affected families are available to demonstrate lack of segregation with disease.
BP1	Not met	Insufficient data to determine whether FGF3 disease is caused primarily by truncating variants rather than missense variants. The available gene-level data from the PVS1 gene context support loss-of-function as a disease mechanism but do not establish that missense variants are an uncommon cause of FGF3-related disease.	pvs1_gene_context
BP2	Not met	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).
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a missense substitution.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No data on observation of this variant in a case with an alternate molecular basis for disease are available.
BP6	Not met	This variant is absent from ClinVar. No reputable source has reported this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (NP_005238.1:p.Pro208His), not a synonymous variant.
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. No trans-phase data available and FGF3 is not established as a recessive disease gene in this context.
PM4	N/A	PM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss). This is a missense substitution.

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