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FGFR1
Final classification
Likely Pathogenic
PVS1PM2BP4
FGFR1
c.1746C>A
p.Cys582Ter
nonsense · exon 13
Gene context NCBI Gene ↗ OncoKB ↗

FGFR1 encodes a receptor tyrosine kinase in the fibroblast growth factor receptor family; when bound by fibroblast growth factors, it activates signaling cascades such as the PI3K/AKT and MAPK pathways that drive cell growth, differentiation, and embryonic development. Germline changes in FGFR1 are associated with congenital conditions including Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and Kallmann syndrome 2, and chromosomal rearrangements involving the gene are linked to certain blood disorders. FGFR1 also functions as an oncogene: activating alterations occur in cancers of the lung, breast, prostate, head and neck, and esophagus, and FGF signaling can contribute to treatment resistance, making the receptor a target for small-molecule inhibitor drugs.

This variant

FGFR1-related developmental disorders such as Hartsfield syndrome arise from loss of FGFR1 function, and this truncating variant is predicted to eliminate the tyrosine kinase domain. The Likely Pathogenic classification is therefore consistent with a germline loss-of-function mechanism, in contrast to the activating FGFR1 alterations that act as oncogenic drivers in certain cancers.

Transcript
NM_001174067.1
HGVS · transcript:coding
NM_001174067.1:c.1746C>A
GRCh38
chr8:38417316 G>T
GRCh37
chr8:38274834 G>T
Basis Likely Pathogenic: PVS1 (Very Strong) for the truncating nonsense variant, supported by PM2 (variant absent from population databases) and BP4 (no predicted splice impact). ▾
Likely Pathogenic: PVS1 (Very Strong) for the truncating nonsense variant, supported by PM2 (variant absent from population databases) and BP4 (no predicted splice impact).
Classification rationale
PVS1PM2 BP4 Likely Pathogenic
FGFR1 c.1746C>A nonsense · exon 13

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.

PVS1 + PM2 + BP4 → Likely Pathogenic
Gene diagram · NM_001174067.1 · variants mapped to exon structure
FGFR1 NM_001174067.1
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
Met (Very Strong): nonsense change p.(Cys582Ter) is predicted to trigger nonsense-mediated decay, eliminating the tyrosine kinase domain.
pvs1_gene_context.json: targeted germline literature review found FGFR1 loss-of-function is a supported disease mechanism (FGFR1-Related Hartsfield Syndrome), gating generic PVS1 framework eligibility (pvs1_gene_gate: eligible).pvs1_variant_assessment.json: classifies the variant as a nonsense/consequence_class 'nonsense' change, applies the generic PVS1 framework (framework_cite: pvs1_generic_framework, PMC6185798), with suggested_default_strength PVS1 pending confirmation of transcript relevance, NMD status, and exon importance.Mutalyzer/VariantValidator prefetch normalization data: protein consequence NP_001167538.1:p.(Cys582Ter); reference protein length 854 aa (position_last_original: 854); PTC at residue 582 (position_last_predicted: 582); VariantValidator variant_exonic_positions place the variant in exon 13 (both GRCh37 NC_000008.10 and GRCh38 NC_000008.11), well upstream of the terminal exon 18, supporting NMD prediction per the >50bp/not-last-exon rule.
pvs1_generic_framework ↗
✓
PM2 supporting Pathogenic
Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.
The normalized GRCh37 allele 8-38274834-G-T is absent from gnomAD v2.1.The normalized GRCh38 allele chr8-38417316-G-T is absent from gnomAD v4.1 and gnomAD-Canada v1.0.No FGFR1 VCEP/ClinGen gene-specific population-frequency specification was retrieved; generic ACMG/AMP population evidence is therefore used.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP4 supporting Benign
Met (Supporting): no predicted splice impact (SpliceAI max delta 0.00), below the calibrated damaging-splicing threshold.
SpliceAI/Pangolin lookup (spliceai source) shows max delta score = 0.00 (pangolin_SG = 0.005, pangolin_SL = -0.141) for NM_001174067.1:c.1746C>A, indicating no predicted splice-altering effect.SpliceAI's calibrated delta-score framework (Jaganathan et al. 2019, PMID 30661751) supports treating scores at or near 0.00 as evidence against a splice-altering effect.This is a nonsense (stop-gain) variant (NP_001167538.1:p.(Cys582Ter)) located mid-exon (exon boundaries c.1701-1846 per selector data), not at a canonical splice site, consistent with the null SpliceAI prediction.
spliceai ↗
Assessed · not applied · 5 not met · 12 not assessed
Pathogenic
PS2 Not assessed: no proband phenotype or parental genotype data were available to evaluate confirmed de novo occurrence.
PS3 Not assessed: no functional assay data (e.g., kinase activity or receptor signaling) for this variant were available.
PS4 Not assessed: no affected-case series or case-control enrichment data for this variant were available.
PM3 Not assessed: no observation of this variant in trans with a pathogenic FGFR1 variant was available.
PM6 Not assessed: no case report establishes de novo occurrence of this variant with untested parents.
PP1 Not assessed: no family pedigree, relative genotypes, or segregation data were available.
PP3 Not met: no predicted splice impact (max delta 0.00) and no other computational evidence of a damaging effect.
PP4 Not assessed: no proband phenotype or phenotype-specificity evidence was provided.
PP5 Not met: ClinVar has no exact-variant record, so no expert-panel pathogenic assertion exists.
Benign
BA1 Not met: the variant is absent from population databases, so no allele frequency supports a benign common-variant call.
BS1 Not met: absent from gnomAD datasets, with no allele frequency exceeding the expected threshold.
BS2 Not assessed: no healthy-adult carrier observations of this allele were reported.
BS3 Not assessed: no functional assay data demonstrating normal (benign) function for this variant were available.
BS4 Not assessed: no informative relatives with confirmed phenotype and genotype were reported.
BP2 Not assessed: no observation of this variant with another pathogenic FGFR1 variant in cis or trans was available.
BP5 Not assessed: no independent molecular diagnosis explaining the phenotype was provided.
BP6 Not met: ClinVar has no exact-variant record, so no expert-panel benign assertion exists.
N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots