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FGF3c.623C>AUncertain significance
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Variant interpretation report

FGF3 c.623C>A, p.(Pro208His)

NM_005247.2:c.623C>A NP_005238.1:p.(Pro208His) 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 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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

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; 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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV107388255, n = 1 times).

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 · 21 not met · 0 not assessed · 6 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

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).

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 exomes.
  • Absent from gnomAD v4.1 (0/1
  • 568
  • 532 alleles
  • AF=0.0).
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.214 (benign
  • below 0.5 threshold).
  • BayesDel score -0.393656 (benign
  • negative score).
  • SpliceAI max delta 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no comparator pathogenic variant at Pro208 identified.
Sources
clinvar ↗
PS2 No de novo occurrence data are available for this variant. No pedigree or trio sequencing data were identified. Details ▾Hide ▴
Still missing
  • No pedigree or de novo sequencing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional evidence.
  • COSMIC COSV107388255: one somatic observation
  • no functional data.
Still missing
  • No functional studies exist for this variant or a systematically characterized range including Pro208.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Still missing
  • No case-control or prevalence data available.
PM1 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. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: no statistically significant hotspot at FGF3 Pro208.
  • ClinVar: no pathogenic variants reported at codon 208.
Still missing
  • No functional domain data specific to FGF3 residue 208.
Sources
clinvar ↗
PM5 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. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variants identified in ClinVar.
Sources
pm5_candidates
PM6 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. Details ▾Hide ▴
Still missing
  • No de novo sequencing or pedigree data available.
PP1 No co-segregation data in affected families are available for this variant. Details ▾Hide ▴
Still missing
  • No family co-segregation data available.
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. No gnomAD missense constraint metrics (e.g., missense Z-score) or gene-level missense burden data were available for this assessment. Details ▾Hide ▴
Still missing
  • No FGF3 missense constraint or burden data available to evaluate PP2.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.214 (benign
  • below 0.5 threshold).
  • BayesDel score -0.393656 (benign
  • negative score).
  • SpliceAI max delta 0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Still missing
  • No patient phenotype data available.
PP5 This variant is absent from ClinVar. No reputable source has reported this variant as pathogenic. No ClinVar 3-star expert panel classification exists. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic assertion from any submitter.
Sources
clinvar ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Global AF = 0.0 in gnomAD v4.1
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Global AF = 0.0 in gnomAD v4.1
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Still missing
  • No trans-phase or homozygous observation data available.
Sources
gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no damaging effect were identified for this variant. No experimental data characterize the functional impact of p.Pro208His. Details ▾Hide ▴
Still missing
  • No functional studies exist for p.Pro208His.
Sources
oncokb ↗
BS4 No segregation data in affected families are available to demonstrate lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP1 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. Details ▾Hide ▴
Evidence considered
  • FGF3 LoF disease mechanism is supported
  • but no data establish truncating-only disease architecture for BP1.
Still missing
  • No FGF3 variant spectrum data to assess truncating vs. missense predominance.
Sources
pvs1_gene_context
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). Details ▾Hide ▴
Still missing
  • No trans/cis phase data available.
BP5 No data on observation of this variant in a case with an alternate molecular basis for disease are available. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers.
BP6 This variant is absent from ClinVar. No reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign assertion from any submitter.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 208 (Pro→His)
  • not a null variant.
  • Gene-level FGF3 loss-of-function disease mechanism is supported (eligible for PVS1 in principle)
  • but variant type does not satisfy null-variant requirement.
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM3 N/APM3 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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss). This is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (NP_005238.1:p.Pro208His), not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a criterion in the generic ACMG/AMP 2015 framework (PMID:25741868). No applicable standard exists for assessment under the current framework mode. Details ▾Hide ▴
Sources
generic_acmg_combination_rules

Identifiers

Gene
FGF3
Transcript
NM_005247.2
Coding (HGVS c.)
NM_005247.2:c.623C>A
Protein (HGVS p.)
NP_005238.1:p.(Pro208His)
GRCh38
chr11:69810402 G>T
GRCh37
chr11:69625170 G>T
COSMIC
COSV107388255

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 0 / 1,568,532 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,568,532 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -56 bp
0.000
SpliceAI acceptor gainat +65 bp
0.000
SpliceAI donor lossat +16 bp
0.000
SpliceAI donor gainat +165 bp
0.000
Pangolin splice lossmagnitude shown
-0.120
Pangolin splice gain
0.000

Other predictors

REVEL
0.214
BayesDel
-0.394

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.214 (benign
  • below 0.5 threshold).
  • BayesDel score -0.393656 (benign
  • negative score).
  • SpliceAI max delta 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.214 (benign
  • below 0.5 threshold).
  • BayesDel score -0.393656 (benign
  • negative score).
  • SpliceAI max delta 0.00 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (NP_005238.1:p.Pro208His), not a synonymous variant. 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 = 0.214. BayesDel score = -0.393656.

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 0 / 1,568,532 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= 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).

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 = 0.214. BayesDel score = -0.393656.

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 previously been reported in somatic cancers (COSMIC; COSV107388255, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.