NM_001174067.1:c.475G>A

FGFR1 · NP_001167538.1:p.(Glu159Lys) · NM_001174067.1

GRCh37: chr8:38285936 C>T · GRCh38: chr8:38428418 C>T

Gene: FGFR1 Transcript: NM_001174067.1

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

FGFR1

Transcript

NM_001174067.1

Protein

NP_001167538.1:p.(Glu159Lys)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting) is met: NM_001174067.1:c.475G>A is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency 0%).

BP4 (supporting benign) is met: multiple lines of in silico evidence suggest no deleterious impact, including SpliceAI max delta 0.03 (no splicing effect), BayesDel 0.049 (benign range), and REVEL 0.522 (indeterminate).

PVS1 is not applicable: c.475G>A is a missense variant (p.Glu159Lys) and does not meet the null-variant criteria required for PVS1 assessment per ClinGen SVI PVS1 recommendations (PMC6185798).

PS3/BS3 not assessed: no well-established functional studies were identified for this variant. OncoKB reports Unknown Oncogenic Effect.

PP5/BP6 not assessed: ClinVar submissions were matched to a different variant (NM_023110.3:c.742G>A, p.Val248Met) and all are non-exact matches; no expert panel or reputable source classification exists for this specific variant.

PS4 not met: variant is rare (absent from gnomAD) but no case-control enrichment data are available to establish statistically significant association with disease.

PP3 not met: combined in silico evidence (REVEL 0.522, BayesDel 0.049, SpliceAI max delta 0.03) does not support a deleterious effect.

No publications reviewed (PMIDs: 21082653, 20301509, 20301628, 28492532) mention the specific variant NM_001174067.1:c.475G>A. All are gene-level reviews or methodology papers without variant-specific evidence.

Final classification: Uncertain Significance (VUS). One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, yielding conflicting evidence that does not meet the threshold for Likely Pathogenic, Likely Benign, Pathogenic, or Benign classification under generic ACMG/AMP 2015 combination rules (PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_001174067.1:c.475G>A is a missense variant (p.Glu159Lys); it does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 assessment per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No data available on a known pathogenic variant with the same amino acid change at the same residue (Glu159). A pathogenic variant at the same position is required for PS1 assessment.
PS2	Not assessed	No de novo observation data available for this variant. PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed.
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific curated functional evidence. No publications with functional data mention NM_001174067.1:c.475G>A.	oncokb
PS4	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada), indicating rarity, but no case-control enrichment data or cohort prevalence data are available to establish statistically significant enrichment in affected individuals. ClinVar submissions were matched to a different variant (NM_023110.3:c.742G>A) and are not usable. Rarity alone is insufficient to meet PS4.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	Not assessed	PS5 requires a different pathogenic variant at the same amino acid position identified in trans with a pathogenic variant (for recessive disorders), or a de novo observation not meeting PS2 criteria. No such data are available for this variant.
PM1	Not assessed	PM1 requires location in a mutational hot spot or critical functional domain without benign variation. This variant (p.Glu159Lys) lies in the extracellular Ig-like domain of FGFR1, but no VCEP/CSPEC framework defines PM1 criteria for FGFR1, and the variant is not in a statistically significant hotspot per CancerHotspots.org. Domain-level PM1 assessment cannot be made without gene-specific guidance.
PM2	Met	NM_001174067.1:c.475G>A is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency is 0% in all populations, meeting the non-VCEP PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with different amino acid changes were identified in ClinVar or other databases. PM5 candidate harvesting returned zero candidates.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity.
PP1	Not assessed	No segregation data available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not assessed	PP2 is applicable when a missense variant occurs in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. While FGFR1 missense variants are a known disease mechanism (e.g., craniosynostosis, Hartsfield syndrome), no HCI prior score or gene-specific missense constraint metric is available to assess the rate of benign missense variation in FGFR1.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.522 (below typical 0.7 pathogenic threshold), BayesDel score is 0.049 (strongly in benign range; well below the ~0.27 pathogenic threshold), and SpliceAI max delta score is 0.03 (no predicted splicing impact). The combined in silico evidence is contradictory or favors a benign interpretation.	revel bayesdel spliceai
PP4	Not assessed	No variant-specific phenotype or clinical data for the proband are available. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not assessed	No reputable source has classified this variant as pathogenic. ClinVar submissions were matched to a different variant (NM_023110.3:c.742G>A, p.Val248Met) and all submissions are non-exact matches; no expert panel classification exists for this variant. None of the ClinVar-associated PMIDs (21082653, 20301509, 20301628, 28492532) were found to mention NM_001174067.1:c.475G>A.
BA1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). BA1 requires an allele frequency >1% (non-VCEP threshold). Allele frequency is 0% in all populations examined.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). BS1 requires an allele frequency >0.3% for a dominant disorder (non-VCEP threshold). Allele frequency is 0% in all populations examined.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder. The variant is absent from all population databases, but absence from population databases alone does not constitute observation in confirmed healthy adults; the absence could reflect rarity rather than pathogenicity.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrate no damaging effect on protein function or splicing for this variant. OncoKB reports Unknown Oncogenic Effect but provides no benign functional evidence.	oncokb
BS4	Not assessed	No segregation data are available to assess lack of cosegregation with disease. BS4 requires non-segregation with disease in affected family members.
BP1	Not assessed	BP1 applies to missense variants in genes where only truncating variants are a known disease mechanism. FGFR1 has both missense and truncating pathogenic variants (e.g., missense variants cause craniosynostosis and Hartsfield syndrome), so BP1 does not clearly apply. Without gene-specific VCEP guidance, BP1 is not assessed.
BP2	Not assessed	BP2 requires observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a recessive disorder. No trans or cis phase data are available for this variant.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact. SpliceAI predicts no splicing impact (max delta score 0.03, well below 0.1 threshold). BayesDel score of 0.049 is strongly in the benign range (well below ~0.27 pathogenic threshold). REVEL score of 0.522 is indeterminate but below the typical 0.7 threshold for pathogenic prediction. The preponderance of in silico evidence supports a benign interpretation.	spliceai bayesdel revel
BP5	Not assessed	BP5 requires observation of this variant in a case with an alternate molecular basis for disease. No such data are available.
BP6	Not assessed	BP6 requires a reputable source to classify the variant as benign. ClinVar submissions were matched to a different variant (NM_023110.3:c.742G>A, p.Val248Met) and are non-exact matches; therefore, they cannot be used for BP6 assessment of this variant.
BP7	N/A	BP7 applies specifically to synonymous (silent) variants with no predicted splice impact. NM_001174067.1:c.475G>A is a missense variant (p.Glu159Lys), not a synonymous variant. BP7 is not applicable to missense variants.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is a single-nucleotide substitution, not an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders and requires observation in trans with a pathogenic variant. FGFR1-related disorders (Hartsfield syndrome) can show autosomal dominant inheritance; without a confirmed recessive context for this variant, PM3 is not applicable.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This variant is a missense substitution, not a protein-length-altering variant.

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