LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-09
Case ID: NM_000142.4_c.1172C_T_20260809_032453
Framework: ACMG/AMP 2015
Variant classification summary

NM_000142.4:c.1172C>T

FGFR3  · NP_000133.1:p.(Ala391Val)  · NM_000142.4
GRCh37: chr4:1806153 C>T  ·  GRCh38: chr4:1804426 C>T
Gene: FGFR3 Transcript: NM_000142.4
Final call
Likely Pathogenic
PM1 moderate PM5 moderate PM2 supporting PP2 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
FGFR3
Transcript
NM_000142.4
Protein
NP_000133.1:p.(Ala391Val)
gnomAD AF
7.441805084241233e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Inconclusive
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM1 (Moderate): residue 391 lies in the FGFR3 transmembrane domain, a critical functional domain with multiple established disease-causing mutations.
2
PM5 (Moderate): p.Ala391Glu, a different missense change at the same residue, is a well-established recurrent pathogenic mutation causing Crouzon syndrome with acanthosis nigricans.
3
PM2 (Supporting): gnomAD v4.1 allele frequency is 0.00074% with zero homozygotes, well below the 0.1% threshold.
4
PP2 (Supporting): missense mutations are the dominant mechanism of FGFR3 germline disease.
5
BP4 (Supporting): all computational predictors indicate no impact (SpliceAI 0.01, REVEL 0.162, BayesDel -0.317).
6
Final classification: Likely Pathogenic, per the generic ACMG/AMP rule of 2 moderate + 2 supporting pathogenic criteria (PM1, PM5, PM2, PP2); the lone supporting benign criterion (BP4) does not reach a benign or likely-benign threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback (no FGFR3 VCEP/CSPEC available), the combination of 2 moderate (PM1, PM5) + 2 supporting (PM2, PP2) pathogenic criteria satisfies the '2 Moderate and 2 Supporting' Likely Pathogenic rule, and the single supporting benign criterion (BP4) fails to meet any benign or likely-benign combination, yielding a final call of Likely Pathogenic.
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: this is a missense change, so no null-variant mechanism (nonsense-mediated decay, truncation) is triggered.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: the established pathogenic change at residue 391 is p.Ala391Glu, a different amino acid change from this p.Ala391Val.
clinvar PMID:11426459 PMID:8880573
PS2 Not assessed Not assessed: no parental-testing data exists for this exact variant.
clinvar PMID:8880573 PMID:11426459 PMID:20199409 PMID:7493034
PS3 Not assessed Not assessed: no functional study of this variant was available.
oncokb PMID:34272467 PMID:29533785
PS4 Not assessed Not assessed: no case-control or cohort prevalence study of this exact variant was available.
PMID:11426459 PMID:7493034 PMID:8880573 PMID:20199409 PMID:29533785 PMID:34272467 clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM1 Met Met (moderate): residue 391 lies in the FGFR3 transmembrane domain, a critical functional domain harboring multiple disease-causing mutations.
PMID:11426459 PMID:8880573 gnomad_v4
PM2 Met Met (supporting): gnomAD v4.1 allele frequency is 0.00074% with zero homozygotes, far below the 0.1% PM2 threshold.
gnomad_v2 gnomad_v4 gnomad_canada
PM3 N/A Not applicable: this criterion requires a recessive disorder, and FGFR3 disease here is autosomal dominant.
PM4 N/A Not applicable: this missense change does not alter protein length.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Met Met (moderate): a different missense change at the same residue, p.Ala391Glu, is a well-established recurrent pathogenic mutation causing Crouzon syndrome with acanthosis nigricans.
PMID:8880573 PMID:11426459 PMID:20199409 clinvar gnomad_v4
PM6 Not assessed Not assessed: no de novo evidence for this exact variant was available.
clinvar PMID:8880573 PMID:20199409
PP1 Not assessed Not assessed: no co-segregation data for this exact variant was available.
clinvar PMID:8880573 PMID:11426459 PMID:7493034
PP2 Met Met (supporting): missense mutations are the established dominant mechanism of FGFR3 germline disease.
PMID:11426459 PMID:8880573 PMID:20199409 gnomad_v4
PP3 Not met Not met: all computational tools predict no impact (SpliceAI 0.01, REVEL 0.162, BayesDel -0.317).
spliceai revel bayesdel
PP4 Not assessed Not assessed: no proband phenotype or family-history data was available.
clinvar PMID:11426459 PMID:20199409 PMID:8880573 PMID:7493034
PP5 Not met Not met: no ClinVar expert-panel classification exists for this variant.
clinvar generic_acmg_combination_rules
BA1 Not met Not met: highest allele frequency is 0.0165%, far below the 1% BA1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met Not met: highest allele frequency is 0.0165%, below the 0.3% BS1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not met Not met: no homozygotes are observed and carriers lack phenotype-verified healthy-adult documentation.
gnomad_v2 gnomad_v4 clinvar
BS3 Not assessed Not assessed: no functional study demonstrating a lack of damaging effect was available.
oncokb spliceai PMID:34272467 PMID:29533785
BS4 Not assessed Not assessed: no non-segregation evidence for this exact variant was available.
clinvar gnomad_v2 gnomad_v4
BP1 Not met Not met: FGFR3 germline disease is caused by activating missense mutations, not truncating variants.
PMID:11426459 PMID:8880573 pvs1_gene_context
BP2 Not assessed Not assessed: no trans/cis phase data with a pathogenic variant was available.
BP3 N/A Not applicable: this missense change involves no in-frame indel in a repetitive region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met (supporting): all three computational lines predict no impact (SpliceAI 0.01, REVEL 0.162, BayesDel -0.317).
spliceai revel bayesdel
BP5 Not assessed Not assessed: no proband-level data was available to evaluate an alternate molecular basis.
clinvar
BP6 Not met Not met: no ClinVar expert-panel benign classification exists for this variant.
clinvar generic_acmg_combination_rules
BP7 N/A Not applicable: this criterion applies only to synonymous variants, and this is a missense change.
generic_acmg_combination_rules
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