0%
FGFR1c.2242C>TUncertain significance
Print report
Variant interpretation report

FGFR1 c.2242C>T, p.(His748Tyr)

NM_001174067.1:c.2242C>T NP_001167538.1:p.(His748Tyr) 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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Under generic ACMG/AMP thresholds, complete absence from population databases supports PM2 at a supporting level (allele frequency <0.1% for dominant disorders).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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; combination = 1 supporting, 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Likely benign.

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
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV58334750, n = 2 times).

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: 1 met · 21 not met · 0 not assessed · 7 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

NM_001174067.1:c.2242C>T (p.His748Tyr) is a missense variant in exon 17 of FGFR1, encoding the tyrosine kinase domain.

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting PM2 at a supporting level under generic ACMG/AMP thresholds.

No other pathogenic or likely pathogenic criteria were met. PVS1 is not applicable (missense, not a null variant). PS1 and PM5 could not be assessed because no pathogenic comparator missense at codon 748 was identified. PS3/BS3 were not met due to absence of variant-specific functional data; OncoKB reports 'Unknown Oncogenic Effect.' PS4 was not met because no case-control or cohort data exist. PP3/BP4 were not met due to equivocal in silico predictions (REVEL 0.648 vs. BayesDel 0.129). PP5/BP6 were not met because no reputable source has classified this specific variant, and the ClinVar match was to a different variant on a different transcript.

With only one supporting pathogenic criterion (PM2) met and no benign criteria met, the variant does not reach a classifiable tier under ACMG/AMP 2015 combination rules. The evidence is insufficient to classify this variant as pathogenic, likely pathogenic, benign, or likely benign. The variant is therefore a Variant of Uncertain Significance (VUS).

Met · 1

PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Under generic ACMG/AMP thresholds, complete absence from population databases supports PM2 at a supporting level (allele frequency <0.1% for dominant disorders). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Still missing
  • Coverage at this locus in gnomAD is not reported
  • reduced coverage could mask true population frequency.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS1 No evidence that a different missense change at the same codon (His748) has been established as pathogenic. ClinVar candidate search for same-residue comparator variants returned no candidates. The only ClinVar match was to an unrelated synonymous variant on a different transcript (NM_023110.3:c.2248C>T, p.Leu750=). Details ▾Hide ▴
Evidence considered
  • No pathogenic missense comparator at codon 748 identified in ClinVar or literature.
Still missing
  • No comprehensive search for pathogenic variants at His748 across all databases.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation reported for this variant. No parental data or confirmed maternity/paternity data were available in any reviewed source. Details ▾Hide ▴
Evidence considered
  • No de novo data identified for NM_001174067.1:c.2242C>T.
Still missing
  • No trio or parental genotype data were available for review.
PS3 No well-established functional studies demonstrating a deleterious effect were identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence. No published functional studies mentioning c.2242C>T or p.His748Tyr were found in the literature sources reviewed. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies found in literature.
Still missing
  • No in vitro or in vivo functional characterization of p.His748Tyr has been performed.
Sources
oncokb ↗
PS4 No case-control data demonstrating enrichment of this variant in affected individuals versus controls. The ClinVar record matched was for a different variant (NM_023110.3:c.2248C>T, synonymous) and is not usable. No cohort studies or case series specifically reporting NM_001174067.1:c.2242C>T were identified. Details ▾Hide ▴
Evidence considered
  • ClinVar match was to a different variant (c.2248C>T
  • synonymous)
  • not usable for PS4. No case reports or cohort studies found.
Still missing
  • No affected-individual counts available for this variant.
Sources
clinvar ↗
PM1 This variant (p.His748Tyr) is not located in a statistically significant mutational hotspot. Cancer Hotspots analysis confirmed the residue is not significant. COSMIC reports only 2 somatic observations. Although His748 lies within the FGFR1 tyrosine kinase domain, there is no evidence that missense variants at this specific residue are enriched in affected individuals versus the general population. Details ▾Hide ▴
Evidence considered
  • Not in a cancer hotspot
  • 2 somatic COSMIC observations
  • residue not statistically enriched for pathogenic missense.
Still missing
  • No domain-specific constraint or regional missense enrichment data were available.
PM6 No de novo observation without confirmation of paternity and maternity is reported for this variant. PM6 requires a de novo report, which is absent from all reviewed sources. Details ▾Hide ▴
Evidence considered
  • No de novo report for NM_001174067.1:c.2242C>T identified.
Still missing
  • No trio sequencing data available.
PP1 No cosegregation data are available for this variant. No family studies or pedigrees with NM_001174067.1:c.2242C>T were identified in any reviewed source. Details ▾Hide ▴
Evidence considered
  • No cosegregation data identified.
Still missing
  • No family genotype data available for cosegregation analysis.
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While missense variants are a recognized mechanism in FGFR1-related disorders (Hartsfield syndrome, craniosynostosis), region-specific missense constraint data (e.g., missense Z-score or gnomAD constraint metrics for the FGFR1 kinase domain) were not available to establish a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • FGFR1 missense variants are a known disease mechanism
  • but missense constraint data are unavailable to satisfy PP2.
Still missing
  • No gene-level or domain-level missense constraint metrics (e.g.
  • gnomAD Z-score
  • missense OE ratio) were assessed.
PP3 In silico predictions are equivocal. REVEL score is 0.648 (above the 0.5 midpoint, leaning pathogenic but below the typical 0.75 threshold for PP3). BayesDel score is 0.129 (below typical pathogenicity thresholds, leaning benign). SpliceAI delta score is 0.00 (no predicted splice impact). The contradictory signals from REVEL and BayesDel do not constitute multiple concordant lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.648 (weakly pathogenic).
  • BayesDel: 0.129 (leaning benign).
  • SpliceAI max delta: 0.00 (no splice effect).
Still missing
  • No HCI prior score available for FGFR1.
  • Additional in silico predictors (e.g.
  • CADD
  • SIFT
  • PolyPhen-2
  • AlphaMissense) were not assessed.
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data were provided. PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology. No clinical information about the proband was available in any reviewed source. Details ▾Hide ▴
Evidence considered
  • No proband phenotype or family history data available.
Still missing
  • Clinical phenotype of the tested individual is unknown.
PP5 No reputable source has classified this specific variant (NM_001174067.1:c.2242C>T) as pathogenic. The ClinVar record matched by the pipeline is for a different variant (NM_023110.3:c.2248C>T, p.Leu750=, synonymous, classified as Likely benign) and is marked as not an exact match. The two GeneReviews cited by ClinVar (PMID:20301509 and PMID:20301628) do not mention this variant. No other source classifies this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar match is to a different variant (c.2248C>T
  • synonymous)
  • not usable for PP5. No other source classifies NM_001174067.1:c.2242C>T as pathogenic.
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1% in population databases, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
  • allele frequency is 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 requires an allele frequency >0.3% in population databases, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
  • allele frequency is 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data are available demonstrating observation of this variant in a healthy adult individual for a fully penetrant dominant disorder. BS2 cannot be applied without such evidence. Details ▾Hide ▴
Evidence considered
  • No observation in healthy adult controls documented.
Still missing
  • No healthy adult carrier data available.
BS3 No well-established functional studies demonstrating no deleterious effect were identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional data. No published experimental evidence showing normal function of p.His748Tyr was found in any reviewed source. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional evidence for a benign effect.
Still missing
  • No functional characterization of p.His748Tyr has been performed.
Sources
oncokb ↗
BS4 No cosegregation data are available to demonstrate lack of segregation with disease. BS4 requires absence of cosegregation in affected family members, which cannot be assessed without family genotype data. Details ▾Hide ▴
Evidence considered
  • No family cosegregation data available.
Still missing
  • No multi-generational genotype data available.
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. FGFR1-related disorders (Hartsfield syndrome, craniosynostosis, GnRH deficiency) are known to be caused by missense variants as a primary disease mechanism, including gain-of-function amino acid substitutions in the tyrosine kinase domain. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • FGFR1 missense variants are a well-established disease mechanism
  • BP1 does not apply.
Sources
pvs1_gene_context
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant. BP2 requires such an observation in a fully penetrant dominant disorder, which is absent from all reviewed sources. Details ▾Hide ▴
Evidence considered
  • No data on in trans observation with a pathogenic variant.
Still missing
  • No phasing or compound heterozygosity data available.
BP4 In silico predictions are equivocal. REVEL score is 0.648 (above 0.5, leaning pathogenic), BayesDel is 0.129 (low, leaning benign), and SpliceAI delta is 0.00 (no splice effect). The contradictory signals do not constitute multiple concordant lines of computational evidence suggesting no impact. A single low BayesDel score does not meet BP4 when contradicted by REVEL. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.648 (leaning pathogenic).
  • BayesDel: 0.129 (leaning benign).
  • SpliceAI max delta: 0.00 (no splice effect).
Still missing
  • Additional in silico predictors were not assessed.
Sources
revelbayesdelspliceai ↗
BP5 No evidence was found that this variant was observed in a case with an alternative molecular cause for disease. BP5 requires documentation of an alternative pathogenic variant explaining the phenotype, which is not available. Details ▾Hide ▴
Evidence considered
  • No evidence of an alternative molecular basis for disease in a carrier of this variant.
Still missing
  • No proband genotype data beyond the variant of interest.
BP6 No reputable source has classified this specific variant (NM_001174067.1:c.2242C>T) as benign or likely benign. The ClinVar record matched during prefetch is for a different variant (NM_023110.3:c.2248C>T, p.Leu750=, synonymous) and is marked as not an exact match; its 'Likely benign' classification applies to that variant, not NM_001174067.1:c.2242C>T. Therefore, BP6 cannot be applied. Details ▾Hide ▴
Evidence considered
  • ClinVar match was to a different variant
  • no reputable source classifies NM_001174067.1:c.2242C>T as benign.
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.2242C>T, p.His748Tyr) that does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The variant-level assessment confirmed variant_bucket='other' and apply_generic_pvs1_framework=false per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 748
  • not a predicted null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ASkipped by pre-adjudication directive: trivially not_applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped by pre-adjudication directive: trivially not_applicable. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator missense variants were identified. Automated candidate harvesting returned zero candidates at His748 in ClinVar. PM5 requires a different pathogenic missense change at the same residue, which cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No same-residue missense comparator variants found at His748.
Sources
pm5_candidates
BP3 N/ASkipped by pre-adjudication directive: trivially not_applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.2242C>T, p.His748Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 748
  • BP7 is for synonymous variants only.
PS5 N/APS5 is not a defined criterion in the standard ACMG/AMP 2015 framework (PMID:25741868). No VCEP/CSPEC-specific PS5 definition exists for FGFR1. Cannot be applied under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
  • PS5 is not defined in the governing ACMG/AMP 2015 framework.
Sources
generic_acmg_combination_rules

Identifiers

Gene
FGFR1
Transcript
NM_001174067.1
Coding (HGVS c.)
NM_001174067.1:c.2242C>T
Protein (HGVS p.)
NP_001167538.1:p.(His748Tyr)
GRCh38
chr8:38414189 G>A
GRCh37
chr8:38271707 G>A
ClinVar
3748158
COSMIC
COSV58334750

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

Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.648
BayesDel
0.129

How the predictions were used

PP3 In silico predictions are equivocal. REVEL score is 0.648 (above the 0.5 midpoint, leaning pathogenic but below the typical 0.75 threshold for PP3). BayesDel score is 0.129 (below typical pathogenicity thresholds, leaning benign). SpliceAI delta score is 0.00 (no predicted splice impact). The contradictory signals from REVEL and BayesDel do not constitute multiple concordant lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.648 (weakly pathogenic).
  • BayesDel: 0.129 (leaning benign).
  • SpliceAI max delta: 0.00 (no splice effect).
Still missing
  • No HCI prior score available for FGFR1.
  • Additional in silico predictors (e.g.
  • CADD
  • SIFT
  • PolyPhen-2
  • AlphaMissense) were not assessed.
Sources
revelbayesdelspliceai ↗
BP4 In silico predictions are equivocal. REVEL score is 0.648 (above 0.5, leaning pathogenic), BayesDel is 0.129 (low, leaning benign), and SpliceAI delta is 0.00 (no splice effect). The contradictory signals do not constitute multiple concordant lines of computational evidence suggesting no impact. A single low BayesDel score does not meet BP4 when contradicted by REVEL. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.648 (leaning pathogenic).
  • BayesDel: 0.129 (leaning benign).
  • SpliceAI max delta: 0.00 (no splice effect).
Still missing
  • Additional in silico predictors were not assessed.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.2242C>T, p.His748Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 748
  • BP7 is for synonymous variants only.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.648. BayesDel score = 0.128631.

3 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

  • Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency.
    Adam MP et al. · 1993
    GeneReview discussing isolated gonadotropin-releasing hormone (GnRH) deficiency, which includes FGFR1 as one of many associated genes. NM_001174067.1:c.2242C>T was not identified in this review.
    Does not name this variant
    PMID 20301509 ↗
  • FGFR Craniosynostosis Syndromes Overview.
    Adam MP et al. · 1993
    GeneReview providing an overview of FGFR-related craniosynostosis syndromes involving FGFR1, FGFR2, and FGFR3. NM_001174067.1:c.2242C>T was not identified in this review.
    Does not name this variant
    PMID 20301628 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc is a refinement of the ACMG-AMP variant classification criteria describing a systematic framework for variant interpretation. NM_001174067.1:c.2242C>T is not mentioned in this methods 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 0.000 Open source ↗
ClinVar 1 Likely benign 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 = 0.00). REVEL score = 0.648. BayesDel score = 0.128631.

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 previously been reported in somatic cancers (COSMIC; COSV58334750, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.