NM_001174067.1:c.521C>G

FGFR1 · NP_001167538.1:p.(Thr174Arg) · NM_001174067.1

GRCh37: chr8:38285890 G>C · GRCh38: chr8:38428372 G>C

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.(Thr174Arg)

gnomAD AF

0.00029925353899837423 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

A comprehensive functional screen of 160 FGFR variants (PMID:34272467) did not include Thr174Arg. No variant-specific functional studies have been performed.

FGFR1 variant classification literature (PMID:37805574) establishes domain-based enrichment for IHH-associated missense variants but does not specifically address the Thr174 residue.

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.

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	Missense substitution (c.521C>G, p.Thr174Arg) does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus); generic PVS1 framework is not triggered.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic missense variant at the same amino acid residue (Thr174) with a different nucleotide change has been established. PS1 requires a previously characterized pathogenic variant at the identical amino acid position.	pm5_candidates
PS2	Not assessed	No de novo data are available for this variant. None of the reviewed publications or ClinVar submissions include de novo observations.
PS3	Not met	No well-established functional studies demonstrate a deleterious effect for p.Thr174Arg. OncoKB classifies this variant as Likely Neutral. REVEL (0.263) and BayesDel (−0.147) support a benign or neutral effect. The comprehensive FGFR functional screen (PMID:34272467) evaluated 160 FGFR variants but did not include Thr174Arg.	oncokb revel bayesdel PMID:34272467
PS4	Not met	No case-control data demonstrate statistically significant enrichment of this variant in affected individuals compared to controls. Variant is observed at low frequency in gnomAD (27/278,536 in v2.1; 483/1,614,016 in v4.1) but no disease-specific cohort comparison is available.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	Not met	No reputable source classifies this variant as pathogenic. ClinVar consensus is Uncertain significance from all three submitters. OncoKB classifies as Likely Neutral.	clinvar oncokb
PM1	Not met	Residue Thr174 is located in the extracellular Ig-like domain of FGFR1, not in a recognized mutational hotspot. The hotspots analysis confirms this variant does not lie in a statistically significant hotspot. OncoKB classifies as Likely Neutral. No domain-specific enrichment evidence places Thr174 within a critical functional domain without benign variation.	oncokb
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	Not met	No known pathogenic missense variant at the same amino acid residue (Thr174) has been identified. Automated PM5 candidate harvesting found no same-residue comparator variants in ClinVar.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant. None of the reviewed sources include de novo observations.
PP1	Not met	No segregation data are available for this variant. None of the reviewed publications or ClinVar submissions include co-segregation analysis.
PP2	Not met	PP2 requires a low rate of benign missense variation in the gene. FGFR1 has 334 missense variants reported in gnomAD across all domains. While certain domains show regional enrichment for pathogenic variants (Xu 2023, PMID:37805574), the gene as a whole does not meet the threshold of low benign missense variation rate.	PMID:37805574 gnomad_v2
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.263 (below the typical 0.5 pathogenic threshold), BayesDel score is −0.147 (negative, consistent with benign), and SpliceAI max delta is 0.01 (no predicted splice impact). All in silico predictors suggest a benign or neutral effect.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype or family history data are available for this variant. PP4 requires that the patient's phenotype or family history be highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source classifies this variant as pathogenic. ClinVar consensus is Uncertain significance. OncoKB classifies as Likely Neutral. The GeneReviews cited in ClinVar submissions (PMID:20301509, 20301628, 26937548, 35099867, 38648328) are general gene-level overviews and do not specifically address this variant.	clinvar oncokb
BA1	Not met	Allele frequency is far below the 1% threshold. gnomAD v2.1 AF=0.0097%, gnomAD v4.1 AF=0.03%. This variant is rare in all populations.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is below the 0.3% threshold. gnomAD v2.1 AF=0.0097%, gnomAD v4.1 AF=0.03%. Highest subpopulation frequency is European (non-Finnish) at 0.019%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals are observed in gnomAD. No healthy adult control data with confirmed unaffected status are available for this variant. Without homozygous or confirmed healthy heterozygous carrier data, BS2 cannot be applied.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no deleterious effect for this specific variant. Although OncoKB classifies as Likely Neutral and in silico predictors (REVEL 0.263, BayesDel −0.147) suggest a benign effect, these do not constitute well-established functional studies. The comprehensive FGFR functional screen (PMID:34272467) did not include Thr174Arg.	oncokb revel bayesdel PMID:34272467
BS4	Not met	No segregation or non-segregation data are available for this variant.
BP1	N/A	FGFR1 disease mechanism includes both missense and truncating pathogenic variants. FGFR1-related Hartsfield syndrome, Kallmann syndrome, and craniosynostosis syndromes are all documented to result from missense variants. BP1 is specific to genes where only truncating variants cause disease.	pvs1_gene_context PMID:26937548
BP2	Not met	No data are available regarding observation of this variant in trans with a pathogenic variant. No co-occurrence data exist.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in a case harboring this variant. No such data are available in the reviewed sources.
BP6	Not met	No reputable clinical source classifies this variant as benign. ClinVar consensus is Uncertain significance. OncoKB classifies as Likely Neutral, but OncoKB is a somatic cancer knowledgebase and does not constitute a reputable germline clinical classification source.	clinvar oncokb
BP7	N/A	c.521C>G is a missense variant (p.Thr174Arg), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	In-frame deletions/insertions in a repetitive region without known function — not applicable to this missense substitution.
PM3	N/A	FGFR1-related disorders follow autosomal dominant inheritance. PM3 applies to recessive disorders only.
PM4	N/A	c.521C>G is a single-nucleotide missense substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss).

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