NM_001174067.1:c.1746C>A

FGFR1 · NP_001167538.1:p.(Cys582Ter) · NM_001174067.1

GRCh37: chr8:38274834 G>T · GRCh38: chr8:38417316 G>T

Gene: FGFR1 Transcript: NM_001174067.1

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting BP4 supporting

Variant details

Gene

FGFR1

Transcript

NM_001174067.1

Protein

NP_001167538.1:p.(Cys582Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 (Very Strong): nonsense change p.(Cys582Ter) predicted to trigger nonsense-mediated decay, eliminating the tyrosine kinase domain.

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

BP4 (Supporting): no predicted splice impact (SpliceAI max delta 0.00), below the calibrated damaging-splicing threshold.

Synthesis: PVS1 (Very Strong) combined with PM2 and BP4 (Supporting) yields Likely Pathogenic under the generic ACMG/AMP framework.

Final determination:

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	Met (Very Strong): nonsense change p.(Cys582Ter) is predicted to trigger nonsense-mediated decay, eliminating the tyrosine kinase domain.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Not applicable: this nonsense variant produces no altered amino acid to compare against a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband phenotype or parental genotype data were available to evaluate confirmed de novo occurrence.	final_classification_framework generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay data (e.g., kinase activity or receptor signaling) for this variant were available.
PS4	Not assessed	Not assessed: no affected-case series or case-control enrichment data for this variant were available.
PM1	N/A	Not applicable: PM1 applies to missense variants; this nonsense variant has no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no observation of this variant in trans with a pathogenic FGFR1 variant was available.	final_classification_framework
PM4	N/A	Not applicable: no change in protein length occurs, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no case report establishes de novo occurrence of this variant with untested parents.	final_classification_framework generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no family pedigree, relative genotypes, or segregation data were available.	final_classification_framework generic_acmg_combination_rules
PP2	N/A	Not applicable: PP2 applies to missense variants; no missense change is present to evaluate.	generic_acmg_combination_rules
PP3	Not met	Not met: no predicted splice impact (max delta 0.00) and no other computational evidence of a damaging effect.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-specificity evidence was provided.
PP5	Not met	Not met: ClinVar has no exact-variant record, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency supports a benign common-variant call.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD datasets, with no allele frequency exceeding the expected threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy-adult carrier observations of this allele were reported.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal (benign) function for this variant were available.
BS4	Not assessed	Not assessed: no informative relatives with confirmed phenotype and genotype were reported.	final_classification_framework generic_acmg_combination_rules
BP1	N/A	Not applicable: BP1 applies to missense variants; this nonsense variant falls outside the criterion.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no observation of this variant with another pathogenic FGFR1 variant in cis or trans was available.	final_classification_framework
BP3	N/A	Not applicable: this is not an in-frame indel in a repetitive region, so there is nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): no predicted splice impact (SpliceAI max delta 0.00), below the calibrated damaging-splicing threshold.	spliceai
BP5	Not assessed	Not assessed: no independent molecular diagnosis explaining the phenotype was provided.
BP6	Not met	Not met: ClinVar has no exact-variant record, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this nonsense variant alters the protein sequence.	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.