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FGFR3c.109+2T>CLikely pathogenic
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Variant interpretation report

FGFR3 c.109+2T>C, p.?

NM_000142.4:c.109+2T>C NP_000133.1:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FGFR3

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_000142.4:c.109+2T>C is a canonical splice donor +2 variant in FGFR3. FGFR3 has an established loss-of-function disease mechanism (CATSHL syndrome; camptodactyly, tall stature, scoliosis, hearing loss) in addition to its gain-of-function phenotypes (achondroplasia, thanatophoric dysplasia, hypochondroplasia). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with an established LoF disease mechanism qualify for PVS1. The affected intron 2 donor site is early in the transcript and predicted to result in a null allele via aberrant splicing and nonsense-mediated decay.

PM2Moderate
PM2 · moderate

NM_000142.4:c.109+2T>C is absent from gnomAD v2.1 (0 alleles) and gnomAD v4.1 (0/1,388,290 alleles). AF is 0.000% across all populations, well below the PM2 threshold of <0.1%. This extremely low frequency in large population databases supports a pathogenic role under ACMG/AMP PM2.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

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.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

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

Context only COSMIC ↗
For specialists

Technical detail

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

27 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000142.4:c.109+2T>C is a canonical splice donor +2 variant in FGFR3, a gene with an established loss-of-function disease mechanism (CATSHL syndrome). Under the ClinGen SVI PVS1 framework (PMC6185798), this qualifies for PVS1 at very strong strength.

The variant is absent from gnomAD v2.1 and v4.1 (0/1,388,290 alleles, AF = 0.000%), meeting PM2 at moderate strength.

No benign criteria are met. BA1, BS1, and BS2 are not met as the variant is absent from population databases. No functional studies or segregation data are available. Computational evidence is mixed (SpliceAI delta = 0.00 vs Pangolin SL = -0.54 and BayesDel = 0.61) and does not support BP4.

Applying the generic ACMG/AMP 2015 final classification rules (PMID:25741868): 1 Very Strong (PVS1) + 1 Moderate (PM2) = Likely Pathogenic. Two moderate criteria would be required for Pathogenic; only one moderate criterion is met.

Met · 2

PVS1 Very strongNM_000142.4:c.109+2T>C is a canonical splice donor +2 variant in FGFR3. FGFR3 has an established loss-of-function disease mechanism (CATSHL syndrome; camptodactyly, tall stature, scoliosis, hearing loss) in addition to its gain-of-function phenotypes (achondroplasia, thanatophoric dysplasia, hypochondroplasia). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with an established LoF disease mechanism qualify for PVS1. The affected intron 2 donor site is early in the transcript and predicted to result in a null allele via aberrant splicing and nonsense-mediated decay. Details ▾Hide ▴
Evidence considered
  • Canonical donor +2 splice variant (c.109+2T>C) predicted to abolish the exon 2 donor splice site
  • FGFR3 loss-of-function is an established disease mechanism (CATSHL syndrome)
  • ClinGen SVI PVS1 framework (PMC6185798) supports PVS1 for canonical splice variants in LoF-eligible genes
Still missing
  • FGFR3 has dual disease mechanisms (GoF and LoF)
  • the phenotype of the patient is not available to confirm whether this variant maps to the LoF-associated phenotype
  • Confirm that NM_000142.4 is the biologically relevant transcript for the clinical indication
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_000142.4:c.109+2T>C is absent from gnomAD v2.1 (0 alleles) and gnomAD v4.1 (0/1,388,290 alleles). AF is 0.000% across all populations, well below the PM2 threshold of <0.1%. This extremely low frequency in large population databases supports a pathogenic role under ACMG/AMP PM2. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1 (0/1
  • 388
  • 290 alleles
  • AF = 0.000%)
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo data available. This variant is absent from ClinVar, and no literature was identified reporting de novo occurrence of c.109+2T>C in FGFR3. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no de novo reports identified
Still missing
  • No de novo testing data available
PS3 No functional studies were identified for NM_000142.4:c.109+2T>C or for a systematically characterized range encompassing this splice position. No literature was found for this variant. Details ▾Hide ▴
Evidence considered
  • No variant-specific or range-based functional data in the literature
Still missing
  • No functional studies available
PS4 No case-control or cohort data available. This variant is absent from ClinVar and gnomAD, and no publications were identified reporting affected individuals with c.109+2T>C. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • absent from gnomAD
  • no publication reports of affected individuals
Still missing
  • No case-control or prevalence data
PM6 No de novo reports were identified. No maternity or paternity data confirming de novo status for NM_000142.4:c.109+2T>C was found in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No de novo reports in ClinVar or literature
Still missing
  • No de novo testing available
PP1 No co-segregation data available. No family studies or pedigrees were identified for NM_000142.4:c.109+2T>C. Details ▾Hide ▴
Evidence considered
  • No co-segregation studies identified
Still missing
  • No family segregation data
PP3 Computational evidence is mixed. SpliceAI predicts no significant splice impact (max delta score = 0.00), while Pangolin predicts splice loss (SL = -0.54) and BayesDel scores 0.61 (deleterious). Under PVS1 guidance, PP3 should not be stacked for splice-prediction evidence already captured by PVS1. With SpliceAI showing no effect, multiple lines of computational support for a deleterious splice impact are not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (no predicted splice impact)
  • Pangolin SL score = -0.54 (splice loss prediction)
  • BayesDel score = 0.61 (deleterious)
Still missing
  • SpliceAI predicts no effect
  • conflicting with expectations for a +2 donor variant
Sources
spliceai ↗bayesdel
PP4 No patient phenotype data was provided for assessment. PP4 requires a highly specific phenotype or family history consistent with the gene-disease association. Details ▾Hide ▴
Evidence considered
  • No phenotype data available
Still missing
  • Patient phenotype not available
  • FGFR3 LoF (CATSHL) vs GoF (skeletal dysplasia) phenotype would influence variant interpretation
PP5 NM_000142.4:c.109+2T>C is absent from ClinVar. No reputable source (expert panel or clinical laboratory) has classified this variant, and thus PP5 cannot be applied. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no classification by any submitter
Still missing
  • No ClinVar entry exists for this variant
Sources
clinvar ↗
BA1 Variant is absent from gnomAD (AF = 0.000%, 0/1,388,290 alleles in v4.1). Does not meet the BA1 threshold of >1% allele frequency. Details ▾Hide ▴
Evidence considered
  • AF = 0.000% in gnomAD v4.1
  • far below BA1 threshold of >1%
Sources
gnomad_v4 ↗
BS1 Variant is absent from gnomAD (AF = 0.000%). Does not meet the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴
Evidence considered
  • AF = 0.000% in gnomAD v4.1
  • below BS1 threshold of >0.3%
Sources
gnomad_v4 ↗
BS2 No homozygous individuals were observed in gnomAD (homozygotes = 0 across all populations in v4.1). No evidence of observation in trans with a pathogenic variant. Details ▾Hide ▴
Evidence considered
  • No homozygous observations in gnomAD v4.1 (hom = 0)
Sources
gnomad_v4 ↗
BS3 No well-established functional studies demonstrating a benign effect were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies showing benign effect
Still missing
  • No functional data available
BS4 No segregation data available to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No family segregation data
Still missing
  • No segregation studies available
BP2 No evidence of this variant observed in trans with a pathogenic FGFR3 variant. No data available to meet BP2. Details ▾Hide ▴
Evidence considered
  • No trans observations with pathogenic variants
Still missing
  • No phasing data available
BP4 Multiple lines of computational evidence do not consistently suggest a benign impact. SpliceAI (max delta = 0.00) predicts no splice effect, but this is contradicted by Pangolin (SL = -0.54, predicting splice loss) and BayesDel (0.61, predicting deleteriousness). The evidence is mixed and does not meet the threshold for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no effect)
  • Pangolin SL = -0.54 (splice loss
  • contradictory)
  • BayesDel = 0.61 (deleterious
Still missing
  • Conflicting in silico predictions
  • SpliceAI zero score unusual for +2 variant
Sources
spliceai ↗bayesdel
BP5 No case was identified where an alternative molecular basis for disease was found in an individual harboring this variant. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available
Still missing
  • No case-level data to evaluate alternate etiology
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
Still missing
  • No ClinVar classification available
Sources
clinvar ↗
PS5 No variant-specific functional or mechanistic data were identified to support PS5 at any strength. Details ▾Hide ▴
Evidence considered
  • No variant-specific established data identified
Still missing
  • No functional or mechanistic data for this variant
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: this is a splice variant, not a nucleotide substitution at the same position as a known pathogenic missense variant. Details ▾Hide ▴

No further detail was recorded.

PM1 N/ANot applicable: PM1 is applied to missense variants located in a critical functional domain. This variant is a canonical splice site variant at intron 2 (+2 position), not a coding missense change within a functional domain. The domain-level effect is already captured by PVS1, which accounts for the predicted global loss of FGFR3 function. Details ▾Hide ▴
Evidence considered
  • Splice variant
  • not within a protein functional domain coding sequence
PM5 N/ANot applicable: PM5 requires a different missense variant at the same amino acid residue with a known pathogenic classification. This is a splice variant with an undefined protein consequence (p.?), and no same-residue missense comparators could be identified. Details ▾Hide ▴
Evidence considered
  • Splice variant
  • protein consequence undefined (p.?)
  • PM5 candidate harvesting returned no eligible comparators
PP2 N/ANot applicable: PP2 applies to missense variants in genes where missense variants are a common disease mechanism. This variant is a canonical splice variant, not a missense change. Details ▾Hide ▴
Evidence considered
  • Splice variant
  • PP2 is specific to missense variants
BP1 N/ANot applicable: BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a splice variant, not a missense change. Details ▾Hide ▴
Evidence considered
  • Splice variant
  • BP1 is specific to missense variants
BP3 N/AIn-frame indels in repetitive regions without known function. Not applicable to a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANot applicable: BP7 applies to synonymous or intronic variants not affecting splicing. This is a canonical +2 donor splice variant with predicted splice-altering effect, and is not a synonymous change. Details ▾Hide ▴
Evidence considered
  • Canonical splice variant
  • not a synonymous or deep intronic variant

Identifiers

Gene
FGFR3
Transcript
NM_000142.4
Coding (HGVS c.)
NM_000142.4:c.109+2T>C
Protein (HGVS p.)
NP_000133.1:p.?
GRCh38
chr4:1794045 T>C
GRCh37
chr4:1795772 T>C

Gene diagram

Every interpreted variant in FGFR3, mapped onto the exon structure of NM_000142.4. Select a row to find it on the plot.

FGFR3NM_000142.4
Fetching transcript structure from UCSC…
gnomAD v4.1 0 / 1,388,290 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 / 1,388,290 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%, 0/1388290 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/66958 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.540
Pangolin splice gain
0.050

Other predictors

REVEL
Not available
BayesDel
0.610

How the predictions were used

PP3 Computational evidence is mixed. SpliceAI predicts no significant splice impact (max delta score = 0.00), while Pangolin predicts splice loss (SL = -0.54) and BayesDel scores 0.61 (deleterious). Under PVS1 guidance, PP3 should not be stacked for splice-prediction evidence already captured by PVS1. With SpliceAI showing no effect, multiple lines of computational support for a deleterious splice impact are not met. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (no predicted splice impact)
  • Pangolin SL score = -0.54 (splice loss prediction)
  • BayesDel score = 0.61 (deleterious)
Still missing
  • SpliceAI predicts no effect
  • conflicting with expectations for a +2 donor variant
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence do not consistently suggest a benign impact. SpliceAI (max delta = 0.00) predicts no splice effect, but this is contradicted by Pangolin (SL = -0.54, predicting splice loss) and BayesDel (0.61, predicting deleteriousness). The evidence is mixed and does not meet the threshold for BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no effect)
  • Pangolin SL = -0.54 (splice loss
  • contradictory)
  • BayesDel = 0.61 (deleterious
Still missing
  • Conflicting in silico predictions
  • SpliceAI zero score unusual for +2 variant
Sources
spliceai ↗bayesdel
BP7 N/ANot applicable: BP7 applies to synonymous or intronic variants not affecting splicing. This is a canonical +2 donor splice variant with predicted splice-altering effect, and is not a synonymous change. Details ▾Hide ▴
Evidence considered
  • Canonical splice variant
  • not a synonymous or deep intronic variant

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.61.

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 / 1,388,290 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 ↗

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%, 0/1388290 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/66958 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). BayesDel score = 0.61.

Somatic

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