0%
FGF3c.121G>TUncertain significance
Print report
Variant interpretation report

FGF3 c.121G>T, p.(Gly41Trp)

NM_005247.2:c.121G>T NP_005238.1:p.(Gly41Trp) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About FGF3

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 12 not met · 10 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.00195% (29 alleles)
  • grpmax FAF=1.52e-05. Absent from gnomAD v2.1 and gnomAD-Canada.
Still missing
  • 29 alleles observed in gnomAD v4.1
  • predominantly in NFE population (25/29 alleles)
  • this is a higher absolute count than expected for a highly penetrant dominant disorder allele
  • though frequency remains below threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.432 (below 0.5). BayesDel: -0.07 (benign). SpliceAI: max delta 0.00. Hotspots: not significant.
Sources
revelbayesdelspliceai ↗

Not met · 12 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • ClinVar has no entries for any variant at FGF3 Gly41
  • absent from all databases.
Still missing
  • No comparator variants identified at this residue.
Sources
clinvar ↗
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: no variant-specific functional evidence. No functional studies in literature. REVEL 0.432 and BayesDel -0.07 do not constitute functional evidence for PS3.
Still missing
  • No functional assays performed on this variant or a systematically characterized range including position 41.
Sources
oncokb ↗revelbayesdel
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: not a significant hotspot. No domain-level functional characterization of position 41 in FGF3 was identified.
Still missing
  • No functional domain data for this residue in FGF3.
PM5 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. Details ▾Hide ▴
Evidence considered
  • Zero same-residue comparator variants identified in ClinVar
  • PM5 candidate search returned no candidates.
Still missing
  • No pathogenic comparators at position 41.
Sources
pm5_candidatesclinvar ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.432 (below 0.5 threshold). BayesDel: -0.07 (benign). SpliceAI: max delta 0.00. HCI prior: not available.
Sources
revelbayesdelspliceai ↗
PP5 This variant is absent from ClinVar; no reputable source or expert panel has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar.
Sources
clinvar ↗
BA1 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%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.00195%
  • grpmax FAF=1.52e-05
  • far below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.00195%
  • below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • No functional studies identified. In silico scores alone (REVEL 0.432
  • BayesDel -0.07) do not constitute BS3-level functional evidence.
Still missing
  • No functional assays performed on this variant.
Sources
oncokb ↗revelbayesdel
BP1 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. Details ▾Hide ▴
Evidence considered
  • FGF3 LoF mechanism is supported
  • but no evidence exists that FGF3 disease is exclusively truncation-mediated.
Still missing
  • Unknown whether FGF3 disease is exclusively mediated by truncating variants.
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar.
Sources
clinvar ↗
PS5 This variant is absent from ClinVar; no expert panel or reputable source has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar.
Sources
clinvar ↗

Not assessed · 10 · no assessment recorded

PS2 No de novo data (paternity not confirmed or unconfirmed) are available for this variant in any database or literature source. Details ▾Hide ▴
Still missing
  • No de novo reports found for this variant.
PS4 No case-control data or statistical enrichment analysis is available for this variant in affected individuals versus controls. Details ▾Hide ▴
Still missing
  • No case-control or enrichment studies identified.
PM6 No de novo data (paternity not confirmed or unconfirmed) are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports found.
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No segregation studies identified.
PP2 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. Details ▾Hide ▴
Still missing
  • FGF3 missense constraint metrics not available
  • no established evidence that missense variants are a common mechanism of FGF3-related disease.
PP4 No patient phenotype data are available to assess whether the variant carrier's clinical presentation is specific for FGF3-related disease. Details ▾Hide ▴
Still missing
  • No phenotype data for the proband.
BS2 No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No penetrance or healthy adult carrier data available.
BS4 No segregation data are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No segregation or family studies identified.
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant in FGF3. Details ▾Hide ▴
Still missing
  • No in trans observations identified.
BP5 No data are available regarding an alternate molecular basis for disease in the proband. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data for the proband.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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). Details ▾Hide ▴
Evidence considered
  • Missense variant (Gly41Trp) not eligible for PVS1 null-variant framework.
Sources
pvs1_generic_framework ↗
PM3 N/ASKIP: No data for recessive/trans detection; not applicable for this assessment. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASKIP: This is a substitution variant, not an in-frame deletion/insertion; PM4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AThis is a missense substitution variant, not an in-frame indel in a repetitive region; BP3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.121G>T, p.Gly41Trp), not a synonymous variant; BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
FGF3
Transcript
NM_005247.2
Coding (HGVS c.)
NM_005247.2:c.121G>T
Protein (HGVS p.)
NP_005238.1:p.(Gly41Trp)
GRCh38
chr11:69818813 C>A
GRCh37
chr11:69633581 C>A

Gene diagram

Every interpreted variant in FGF3, mapped onto the exon structure of NM_005247.2. Select a row to find it on the plot.

FGF3NM_005247.2
Fetching transcript structure from UCSC…
gnomAD v4.1 29 / 1,489,482 alleles AF 1.95e-05 · 0 homozygotes · FAF 1.52e-05
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-05 · 29 / 1,489,482 alleles · 0 hom · FAF 1.5e-05
Remaining individuals4 / 57,486 7e-05
European (non-Finnish)25 / 1,126,660 2.2e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.94699e-05; MAF= 0.00195%, 29/1489482 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.95822e-05; MAF= 0.00696%, 4/57486 alleles, homozygotes = 0); grpmax FAF= 1.523e-05.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +91 bp
0.000
SpliceAI acceptor gainat +247 bp
0.000
SpliceAI donor lossat -99 bp
0.000
SpliceAI donor gainat -228 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.432
BayesDel
-0.070

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.432 (below 0.5). BayesDel: -0.07 (benign). SpliceAI: max delta 0.00. Hotspots: not significant.
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.432 (below 0.5 threshold). BayesDel: -0.07 (benign). SpliceAI: max delta 0.00. HCI prior: not available.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.121G>T, p.Gly41Trp), not a synonymous variant; BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.432. BayesDel score = -0.0702942.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 29 / 1,489,482 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.94699e-05; MAF= 0.00195%, 29/1489482 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.95822e-05; MAF= 0.00696%, 4/57486 alleles, homozygotes = 0); grpmax FAF= 1.523e-05.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.432. BayesDel score = -0.0702942.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.