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FGFR1c.475G>AUncertain significance
Print report
Variant interpretation report

FGFR1 c.475G>A, p.(Glu159Lys)

NM_001174067.1:c.475G>A NP_001167538.1:p.(Glu159Lys) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About FGFR1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

1 Likely benign · 1 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR1, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types including lung and breas

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 4 not met · 17 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 SupportingNM_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%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • gnomAD v4.1 (exomes/genomes)
  • and gnomAD-Canada v1.0. Allele count = 0 across all populations.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.03 (no splicing impact). BayesDel 0.049 (benign range). REVEL 0.522 (indeterminate). Combined in silico evidence suggests no impact on gene product.
Sources
spliceai ↗bayesdelrevel

Not met · 4 · evaluated, threshold not reached

PS4 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada v1.0. No case-control or cohort enrichment data available.
Still missing
  • No case-control or cohort prevalence studies for this variant.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.522 (indeterminate/borderline)
  • BayesDel 0.049 (benign range)
  • SpliceAI max delta 0.03 (no splice impact). Combined in silico evidence does not support a deleterious effect.
Sources
revelbayesdelspliceai ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD v2.1
  • v4.1
  • and gnomAD-Canada v1.0. Does not meet BA1 >1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0% in gnomAD v2.1
  • v4.1
  • and gnomAD-Canada v1.0. Does not meet BS1 >0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not assessed · 17 · no assessment recorded

PS1 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. Details ▾Hide ▴
Still missing
  • No same-residue pathogenic comparator variants identified in ClinVar or literature.
PS2 No de novo observation data available for this variant. PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
  • No de novo testing data for this variant.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional studies found.
Still missing
  • No functional assay data for p.Glu159Lys in FGFR1.
Sources
oncokb ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Not in a statistically significant hotspot region. No VCEP-defined PM1 domains for FGFR1.
Still missing
  • No FGFR1-specific PM1 domain criteria available from VCEP/CSPEC.
PM6 No de novo data available for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity. Details ▾Hide ▴
Still missing
  • No de novo testing data for this variant.
PP1 No segregation data available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data for this variant.
PP2 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. Details ▾Hide ▴
Evidence considered
  • FGFR1 missense variants are an established disease mechanism
  • but no HCI prior or missense constraint metric is available to assess benign missense variation rate.
Still missing
  • No HCI prior score or ClinGen missense constraint data for FGFR1.
PP4 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. Details ▾Hide ▴
Still missing
  • No proband clinical phenotype data available.
PP5 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. Details ▾Hide ▴
Evidence considered
  • ClinVar data is non-exact match (matched to NM_023110.3:c.742G>A). No expert panel classification. No publication mentions this variant.
Still missing
  • No expert panel or reputable source classification for this specific variant.
BS2 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD
  • no specific healthy adult observations to assess.
Still missing
  • No observation data in confirmed healthy adults.
BS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect. No functional studies demonstrating benign effect identified.
Still missing
  • No functional assay data for p.Glu159Lys in FGFR1.
Sources
oncokb ↗
BS4 No segregation data are available to assess lack of cosegregation with disease. BS4 requires non-segregation with disease in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data.
BP1 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. Details ▾Hide ▴
Evidence considered
  • FGFR1 disease mechanism includes both missense and truncating pathogenic variants
  • BP1 not clearly applicable.
BP2 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. Details ▾Hide ▴
Still missing
  • No trans-phase or cis-phase observation data.
BP5 BP5 requires observation of this variant in a case with an alternate molecular basis for disease. No such data are available. Details ▾Hide ▴
Still missing
  • No data on alternate molecular basis for disease in carriers of this variant.
BP6 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. Details ▾Hide ▴
Evidence considered
  • ClinVar data is non-exact match
  • no reputable source classifies this variant as benign.
Still missing
  • No expert panel or reputable source benign classification for this specific variant.
PS5 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. Details ▾Hide ▴
Still missing
  • No trans-phase or de novo data for this variant.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
  • Variant class is missense substitution
  • PVS1 decision tree does not apply.
Sources
pvs1_generic_framework ↗
PM3 N/APM3 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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator variants with different amino acid changes were identified in ClinVar or other databases. PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at residue 159 with a different amino acid change identified.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 is not applicable.

Identifiers

Gene
FGFR1
Transcript
NM_001174067.1
Coding (HGVS c.)
NM_001174067.1:c.475G>A
Protein (HGVS p.)
NP_001167538.1:p.(Glu159Lys)
GRCh38
chr8:38428418 C>T
GRCh37
chr8:38285936 C>T
ClinVar
362899

Gene diagram

Every interpreted variant in FGFR1, mapped onto the exon structure of NM_001174067.1. Select a row to find it on the plot.

FGFR1NM_001174067.1
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -331 bp
0.000
SpliceAI acceptor gainat -3 bp
0.030
SpliceAI donor lossat -66 bp
0.000
SpliceAI donor gainat -72 bp
0.010
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.522
BayesDel
0.049

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.03 (no splicing impact). BayesDel 0.049 (benign range). REVEL 0.522 (indeterminate). Combined in silico evidence suggests no impact on gene product.
Sources
spliceai ↗bayesdelrevel
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.522 (indeterminate/borderline)
  • BayesDel 0.049 (benign range)
  • SpliceAI max delta 0.03 (no splice impact). Combined in silico evidence does not support a deleterious effect.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 is not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.522. BayesDel score = 0.0494725.

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Genetic basis of potential therapeutic strategies for craniosynostosis.
    Melville H et al. · 2010
    Review article discussing genetic basis of therapeutic strategies for craniosynostosis, focusing on FGFR1-3 and TWIST1 mutations. NM_001174067.1:c.475G>A was not identified in the abstract or available text of this paper.
    Does not name this variant
    PMID 21082653 ↗
  • Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency.
    Adam MP et al. · 1993
    GeneReviews entry on Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency, discussing FGFR1 mutations in the context of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. NM_001174067.1:c.475G>A was not identified in the abstract or available text of this paper.
    Does not name this variant
    PMID 20301509 ↗
  • FGFR Craniosynostosis Syndromes Overview.
    Adam MP et al. · 1993
    GeneReviews overview of FGFR Craniosynostosis Syndromes, describing FGFR1-3 related craniosynostosis phenotypes. NM_001174067.1:c.475G>A was not identified in the abstract or available text of this paper.
    Does not name this variant
    PMID 20301628 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methods paper describing variant classification framework refinement. NM_001174067.1:c.475G>A was not discussed or evaluated as an example in this paper.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar 1 Likely benign · 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

Error retrieving ClinVar entry.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.522. BayesDel score = 0.0494725.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR1, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types including lung and breas

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.