NM_005247.2:c.121G>T

FGF3 · NP_005238.1:p.(Gly41Trp) · NM_005247.2

GRCh37: chr11:69633581 C>A · GRCh38: chr11:69818813 C>A

Gene: FGF3 Transcript: NM_005247.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

FGF3

Transcript

NM_005247.2

Protein

NP_005238.1:p.(Gly41Trp)

gnomAD AF

1.9469855963348333e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 at supporting: NM_005247.2:c.121G>T (p.Gly41Trp) is present at extremely low frequency in gnomAD v4.1 (AF=0.00195%, 29/1,489,482 alleles, 0 homozygotes, grpmax FAF=1.52e-05) and is absent from gnomAD v2.1 and gnomAD-Canada.

BP4 at supporting_benign: Multiple in silico algorithms predict a benign effect (REVEL 0.432, BayesDel -0.07, SpliceAI max delta 0.00) with no evidence of splicing impact or hotspot localization.

PVS1 is not applicable as this is a missense variant, not a null variant (nonsense, frameshift, or canonical splice site).

No pathogenic or likely pathogenic classification from ClinVar expert panels is available (variant is absent from ClinVar); PS5 and PP5 are not met. PS1 and PM5 are not met as no pathogenic comparator variants exist at residue Gly41.

No variant-specific functional studies, case-control data, segregation data, de novo reports, or phenotype data are available; PS3, PS4, PS2, PM6, PP1, PP4, BS2, BS4, BP2, and BP5 remain not assessed.

BA1 and BS1 are not met as the population frequency (AF=0.00195%) is well below both the 1% and 0.3% thresholds respectively.

Final classification: Variant of Uncertain Significance (VUS). One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, which are offsetting. No other criteria are met. Per generic ACMG/AMP 2015 combination rules, this does not reach the threshold for Likely Pathogenic, Likely Benign, Pathogenic, or Benign.

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	This is a missense variant (c.121G>T, p.Gly41Trp) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic or likely pathogenic variant at the same amino acid position (Gly41) with a different nucleotide change has been identified in ClinVar or the literature to satisfy PS1.	clinvar
PS2	Not assessed	No de novo data (paternity not confirmed or unconfirmed) are available for this variant in any database or literature source.
PS3	Not met	No variant-specific functional data have been identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. No publications with functional characterization of NM_005247.2:c.121G>T were found in the literature pass or full-text review.	oncokb revel bayesdel
PS4	Not assessed	No case-control data or statistical enrichment analysis is available for this variant in affected individuals versus controls.
PS5	Not met	This variant is absent from ClinVar; no expert panel or reputable source has classified it as pathogenic.	clinvar
PM1	Not met	This variant (p.Gly41Trp) does not lie in a statistically significant hotspot per cancerhotspots.org, and no literature was identified characterizing position 41 as a critical functional domain in FGF3.
PM2	Met	This variant is present at extremely low frequency in gnomAD v4.1 (AF=0.00195%, 29/1,489,482 alleles, 0 homozygotes, grpmax FAF=1.52e-05) and is absent from gnomAD v2.1 and gnomAD-Canada. The frequency is well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic or likely pathogenic missense variant at the same amino acid position (Gly41) with a different amino acid change was identified in ClinVar. PM5 candidate harvesting returned zero same-residue candidates.	pm5_candidates clinvar
PM6	Not assessed	No de novo data (paternity not confirmed or unconfirmed) are available for this variant.
PP1	Not assessed	No segregation data are available for this variant.
PP2	Not assessed	No gene-level missense constraint metrics (e.g., gnomAD missense Z-score) or evidence that missense variants are a common disease mechanism for FGF3 are available to assess PP2.
PP3	Not met	In silico predictions do not support a deleterious effect. REVEL score is 0.432 (below the 0.5 threshold for pathogenicity), BayesDel score is -0.07 (negative; predicts benign), and SpliceAI delta score is 0.00 (no splice impact). Multiple computational tools suggest a benign or neutral effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype data are available to assess whether the variant carrier's clinical presentation is specific for FGF3-related disease.
PP5	Not met	This variant is absent from ClinVar; no reputable source or expert panel has classified it as pathogenic.	clinvar
BA1	Not met	The variant's maximum allele frequency in gnomAD v4.1 is 0.00195% (AF=1.95e-05) with grpmax FAF of 1.52e-05, well below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	The variant's allele frequency in gnomAD v4.1 is 0.00195%, below the BS1 threshold of >0.3%. This frequency does not support a benign interpretation under BS1.	gnomad_v4
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age.
BS3	Not met	No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing have been identified for this variant.	oncokb revel bayesdel
BS4	Not assessed	No segregation data are available to assess lack of cosegregation with disease.
BP1	Not met	While FGF3 loss-of-function is supported as a germline disease mechanism, there is no evidence that only truncating variants cause disease in FGF3. BP1 requires a gene where primarily truncating variants are known to cause disease, and this has not been established for FGF3.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a pathogenic variant in FGF3.
BP3	N/A	This is a missense substitution variant, not an in-frame indel in a repetitive region; BP3 is not applicable.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.432 (below deleterious threshold), BayesDel score is -0.07 (predicts benign), and SpliceAI max delta is 0.00 (no predicted splicing impact). The variant is not in a mutational hotspot.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in the proband.
BP6	Not met	This variant is absent from ClinVar; no reputable source has classified it as benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (c.121G>T, p.Gly41Trp), not a synonymous variant; BP7 is not applicable.
PM3	N/A	SKIP: No data for recessive/trans detection; not applicable for this assessment.
PM4	N/A	SKIP: This is a substitution variant, not an in-frame deletion/insertion; PM4 is not applicable.

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