NM_000142.4:c.109+2T>C

FGFR3 · NP_000133.1:p.? · NM_000142.4

GRCh37: chr4:1795772 T>C · GRCh38: chr4:1794045 T>C

Gene: FGFR3 Transcript: NM_000142.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

FGFR3

Transcript

NM_000142.4

Protein

NP_000133.1:p.?

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not applicable: this is a splice variant, not a nucleotide substitution at the same position as a known pathogenic missense variant.
PS2	Not met	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.
PS3	Not met	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.
PS4	Not met	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.
PS5	Not met	No variant-specific functional or mechanistic data were identified to support PS5 at any strength.
PM1	N/A	Not 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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	Not 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.
PM6	Not met	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.
PP1	Not met	No co-segregation data available. No family studies or pedigrees were identified for NM_000142.4:c.109+2T>C.
PP2	N/A	Not 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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not met	No patient phenotype data was provided for assessment. PP4 requires a highly specific phenotype or family history consistent with the gene-disease association.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	Variant is absent from gnomAD (AF = 0.000%). Does not meet the BS1 threshold of >0.3% allele frequency.	gnomad_v4
BS2	Not met	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.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a benign effect were identified for this variant.
BS4	Not met	No segregation data available to assess lack of segregation with disease.
BP1	N/A	Not 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.
BP2	Not met	No evidence of this variant observed in trans with a pathogenic FGFR3 variant. No data available to meet BP2.
BP3	N/A	In-frame indels in repetitive regions without known function. Not applicable to a substitution variant.
BP4	Not met	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.	spliceai bayesdel
BP5	Not met	No case was identified where an alternative molecular basis for disease was found in an individual harboring this variant.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified it as benign or likely benign.	clinvar
BP7	N/A	Not 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.