NM_001174067.1:c.521C>G (p.Thr174Arg) is a missense variant in exon 5 of FGFR1, encoding a substitution of threonine to arginine at codon 174 in the extracellular Ig-like domain. This variant is present at very low frequency in population databases: gnomAD v2.1 (27/278,536 alleles, AF=0.0097%) and gnomAD v4.1 (483/1,614,016 alleles, AF=0.03%), meeting PM2 at the supporting level. It is absent from gnomAD-Canada v1.0.1 Computational predictors unanimously suggest a benign or neutral effect: REVEL score is 0.263 (below the pathogenic threshold), BayesDel is −0.147 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.01), meeting BP4 at the supporting level.2 OncoKB annotates this variant as Likely Neutral. COSMIC records this variant in two somatic cancer samples (COSV58328267), but no germline functional or case-level evidence of pathogenicity is available.3 ClinVar classifies this variant as Uncertain significance (Variation ID: 1024176) based on three submissions, all with criteria provided at the single-submitter level. No expert panel has reviewed this variant.4 A comprehensive functional screen of 160 FGFR variants (PMID:34272467) did not include Thr174Arg. No variant-specific functional studies have been performed.5 FGFR1 variant classification literature (PMID:37805574) establishes domain-based enrichment for IHH-associated missense variants but does not specifically address the Thr174 residue.6 With PM2_supporting and BP4_supporting both met, the evidence is balanced and insufficient to classify this variant as pathogenic or benign. The variant remains a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.7
FGFR1
Final classification
VUS
PM2BP4
FGFR1
c.521C>G
p.Thr174Arg
This variant
NM_001174067.1:c.521C>G (p.Thr174Arg) is a missense variant in exon 5 of FGFR1, encoding a substitution of threonine to arginine at codon 174 in the extracellular Ig-like domain.
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.
Classification rationale
PM2
BP4
VUS
FGFR1 c.521C>G
PM2 + BP4
→
VUS
Gene diagram
· NM_001174067.1 · variants mapped to exon structure
FGFR1
NM_001174067.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases. gnomAD v2.1 allele frequency is 0.0097% (27/278,536 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency is 0.03% (483/1,614,016 alleles, 0 homozygotes), both below the 0.1% threshold for PM2_supporting. Absent from gnomAD-Canada v1.0.
gnomAD v2.1 AF=0.0097% (<0.1%)gnomAD v4.1 AF=0.03% (<0.1%)gnomAD-Canada: absent
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.263 (below the typical pathogenic threshold), BayesDel score is −0.147 (negative, consistent with benign), and SpliceAI predicts no splicing impact (max delta 0.01). All three independent in silico predictors converge on a benign or neutral prediction.
REVEL: 0.263BayesDel: −0.147SpliceAI max delta: 0.01. Three independent predictors all indicate no significant deleterious effect.
Assessed · not applied
· 18 not met · 2 not assessed
Pathogenic
PS1
No known pathogenic missense variant at the same amino acid residue (Thr174) with a different nucleotide change has been established.
PS2
No de novo data are available for this variant.
PS3
No well-established functional studies demonstrate a deleterious effect for p.Thr174Arg.
PS4
No case-control data demonstrate statistically significant enrichment of this variant in affected individuals compared to controls.
PM1
Residue Thr174 is located in the extracellular Ig-like domain of FGFR1, not in a recognized mutational hotspot.
PM5
No known pathogenic missense variant at the same amino acid residue (Thr174) has been identified.
PM6
No de novo data are available for this variant.
PP1
No segregation data are available for this variant.
PP2
PP2 requires a low rate of benign missense variation in the gene.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient-specific phenotype or family history data are available for this variant.
PP5
No reputable source classifies this variant as pathogenic.
Benign
BA1
Allele frequency is far below the 1% threshold.
BS1
Allele frequency is below the 0.3% threshold.
BS2
No homozygous individuals are observed in gnomAD.
BS3
No well-established functional studies demonstrate no deleterious effect for this specific variant.
BS4
No segregation or non-segregation data are available for this variant.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant.
BP5
No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6
No reputable clinical source classifies this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000299254; MAF= 0.02993%, 483/1614016 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000432097; MAF= 0.04321%, 27/62486 alleles, homozygotes = 0); grpmax FAF= 0.00035348.
v2.1
This variant is present in gnomAD v2.1 (AF= 9.69354e-05; MAF= 0.00969%, 27/278536 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000190027; MAF= 0.01900%, 24/126298 alleles, homozygotes = 0); grpmax FAF= 0.00011951.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.03%
· 483 / 1,614,016
0 hom · FAF 0.035%
0 hom · FAF 0.035%
Remaining individuals 27 / 62,486 |
0.043% |
European (non-Finnish) 452 / 1,180,030 |
0.038% |
African/African American 3 / 74,924 |
0.004% |
Ashkenazi Jewish 1 / 29,608 |
0.0034% |
+ 6 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian)
gnomAD v2.1
0.0097%
· 27 / 278,536
0 hom · FAF 0.012%
0 hom · FAF 0.012%
European (non-Finnish) 24 / 126,298 |
0.019% |
Remaining individuals 1 / 7,136 |
0.014% |
African/African American 2 / 24,200 |
0.0083% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
gnomAD Canada 🇨🇦
0.011%
· 2 / 18,418
0 hom · FAF 0.003%
0 hom · FAF 0.003%
European (non-Finnish) 2 / 11,738 |
0.017% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.263. BayesDel score = -0.147005.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58328267, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
34272467 ↗
Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer.
ONCOKB
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
23533228 ↗
Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes.
CLINVAR
37805574 ↗
How human genetic context can inform pathogenicity classification: FGFR1 variation in idiopathic hypogonadotropic hypogonadism.
CLINVAR