LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000142.5:c.746C>G
FGFR3
· NP_000133.1:p.(Ser249Cys)
· NM_000142.5
GRCh37: chr4:1803568 C>G
·
GRCh38: chr4:1801841 C>G
Gene:
FGFR3
Transcript:
NM_000142.5
Final call
Pathogenic
PS4 strong
PS3 moderate
PP3 moderate
PM2 supporting
PM6 supporting
Variant details
Gene
FGFR3
Transcript
NM_000142.5
Protein
NP_000133.1:p.(Ser249Cys)
gnomAD AF
0.0 (v2.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS4 strong is supported by 11/173 affected cases versus 0/238,624 gnomAD alleles.
2
Pathogenic: PS3 moderate functional studies show increased FGFR3 dimerization, phosphorylation, and mutant-dependent growth.
3
Pathogenic: PP3 moderate is supported by REVEL 0.902.
4
Pathogenic: PM2 supporting is supported by absence from gnomAD v4.1 and AF 0 in gnomAD v2.1.
5
Pathogenic: PM6 supporting is supported by an exact-variant de novo report without confirmed maternity and paternity.
Final determination:
Under the generic ACMG/AMP 2015 fallback, one Strong pathogenic criterion plus two Moderate and two Supporting pathogenic criteria supports a Pathogenic classification.
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 | Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PS1 | Not met | Not met: only c.746C>G is documented for pathogenic FGFR3 p.Ser249Cys, with no distinct nucleotide change producing the same amino-acid substitution. |
PMID:25614871
PMID:25606676
PMID:17384684
clinvar
|
| PS2 | Not met | Not met: the variant was reported de novo in affected subject P18, but both maternity and paternity were not confirmed. |
PMID:30692697
|
| PS3 | Met | Met at moderate strength: S249C increased FGFR3 dimerization and phosphorylation, while knockdown reduced mutant-dependent growth and re-expression rescued it. |
PMID:17384684
PMID:25606676
|
| PS4 | Met | Met: 11/173 cases versus 0/238624 gnomAD alleles gives corrected OR 33983.67, 95% CI 1994.12-579146.64, exceeding 5 with the interval above 1. |
PMID:25614871
gnomad_v2
|
| PM1 | Not assessed | Not assessed: a hotspot is reported, but no VCEP-authorized hotspot route or complete evidence for a critical domain without benign variation is available under generic PM1. |
PMID:25614871
clinvar
|
| PM2 | Met | Met at supporting strength: AF was 0 (0/238,624 alleles; 0 homozygotes) in gnomAD v2.1 all-comers exomes and absent from gnomAD v4.1. |
gnomad_v2
gnomad_v4
PMID:25741868
|
| PM3 | N/A | Not applicable: the cited FGFR3 skeletal dysplasias are autosomal dominant, whereas PM3 is restricted to recessive disorders. |
PMID:15772091
|
| PM4 | N/A | Not applicable: PM4 requires a protein-length change, and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PM5 | Not assessed | Not assessed: no different pathogenic missense substitution at FGFR3 residue 249 is documented, and the PM5 candidate review found zero same-residue comparators. |
pm5_candidates
PMID:25614871
clinvar
|
| PM6 | Met | Met at supporting strength: subject P18 had the exact variant and phenotype-consistent thanatophoric dysplasia, reported as de novo without confirmed maternity and paternity. |
PMID:30692697
|
| PP1 | Not assessed | Not assessed: no affected relatives or informative family meioses are reported for the exact variant. |
|
| PP2 | Not assessed | Not assessed: missense disease biology is documented, but no gene-level benign-missense rate demonstrates the two required PP2 conditions together. |
PMID:25614871
PMID:17384684
PMID:25606676
|
| PP3 | Met | Met at moderate strength: REVEL 0.902 meets the generic PP3 moderate threshold of >=0.773 for this missense variant. |
revel
|
| PP4 | Not assessed | Not assessed: the evaluated patient's phenotype and family history are not provided, so disease specificity cannot be judged. |
|
| PP5 | Not met | Not met: ClinVar has no expert-panel submission, and the supporting literature is available for independent evaluation. |
clinvar
|
| BA1 | Not met | Not met: gnomAD v2.1 all-comers exome AF was 0 (0/238,624), below the generic BA1 threshold of >=0.05. |
gnomad_v2
gnomad_v4
|
| BS1 | Not met | Not met: observed AF was 0 in gnomAD v2.1 all-comers exomes and the variant was absent from v4.1, below the generic BS1 default of >=0.01. |
gnomad_v2
gnomad_v4
|
| BS2 | Not assessed | Not assessed: gnomAD showed 0 homozygotes, but no individual-level healthy adult observation or adult health-status evidence was available. |
gnomad_v2
gnomad_v4
|
| BS3 | Not met | Not met: variant-specific assays showed stable dimerization, higher phosphorylation, and mutant-dependent growth rather than no damaging effect. |
PMID:17384684
PMID:25606676
|
| BS4 | Not assessed | Not assessed: no affected family members were evaluated for presence or absence of the variant. |
|
| BP1 | Not met | Not met: FGFR3 disease evidence centers on recurrent activating missense variants, including p.Ser249Cys, rather than primarily truncating variants. |
PMID:25614871
PMID:17384684
PMID:25606676
|
| BP2 | Not assessed | Not assessed: no affected-proband report establishes a pathogenic FGFR3 variant in cis or trans with c.746C>G. |
PMID:17384684
|
| BP3 | N/A | Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| BP4 | Not met | Not met: REVEL 0.902 exceeds the generic BP4 supporting cutoff of <=0.29 for this missense variant. |
revel
|
| BP5 | Not assessed | Not assessed: no patient-level evidence shows an alternate molecular diagnosis explaining the evaluated case. |
|
| BP6 | Not met | Not met: no exact-variant ClinVar expert-panel benign or likely benign classification is present. |
clinvar
|
| BP7 | N/A | Not applicable: BP7 requires a synonymous variant, and this is a missense variant. |
generic_acmg_combination_rules
|
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.