NM_023110.3:c.1368G>T

FGFR1 · NP_075598.2:p.(Met456Ile) · NM_023110.3

GRCh37: chr8:38275808 C>A · GRCh38: chr8:38418290 C>A

Gene: FGFR1 Transcript: NM_023110.3

Final call

VUS

PM2 supporting BP6 supporting

Variant details

Gene

FGFR1

Transcript

NM_023110.3

Protein

NP_075598.2:p.(Met456Ile)

gnomAD AF

0.0005606429862633176 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_023110.3:c.1368G>T (p.Met456Ile) is a missense variant in exon 10 of FGFR1, encoding the tyrosine kinase domain.

This variant is present in gnomAD v2.1 at an allele frequency of 0.041% (115/280,958 alleles, 0 homozygotes) and in v4.1 at 0.056% (905/1,614,218 alleles, 0 homozygotes), with a grpmax filtering allele frequency of 0.069%. While below the formal BS1 threshold of 0.3%, the substantial carrier count in population databases (905 in v4.1) indicates this variant is not a rare private mutation.

In ClinVar, 10 of 11 clinical laboratory submissions classify this variant as Likely benign (7) or Benign (3), with one VUS. No submitter classifies the variant as pathogenic or likely pathogenic. The review status is 'criteria provided, single submitter' without expert panel consensus.

In silico predictions are discordant: REVEL (0.802) predicts damaging, while BayesDel (0.069) and SpliceAI (max delta 0.00) predict benign/no splicing impact. No variant-specific functional studies or case-level observations of pathogenicity were identified in the reviewed literature.

Applying generic ACMG/AMP 2015 combination rules: one supporting benign criterion (BP6) is met. PM2 is met at supporting level for pathogenicity but is substantially weakened by the high carrier count (905 in v4.1). The overall evidence profile favors a likely benign interpretation based on population frequency and multi-laboratory clinical consensus, though the formal BS1 threshold is not crossed.

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_023110.3:c.1368G>T is a missense variant (p.Met456Ile) in exon 10 and does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 variant assessment confirms apply_generic_pvs1_framework is false.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No ClinVar or literature evidence identifies a different nucleotide change at the same codon (c.1368) producing the same amino acid change (p.Met456Ile). PS1 requires a known pathogenic variant at the same position with a different nucleotide substitution.	clinvar pm5_candidates
PS2	Not met	No de novo observation data are available for this variant. ClinVar submissions do not report de novo status, and no reviewed publication documents a confirmed de novo occurrence of NM_023110.3:c.1368G>T.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for p.Met456Ile. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No reviewed publication reports experimental functional data for this variant.	oncokb
PS4	Not met	No case-control study or systematic phenotypic data are available to demonstrate significantly increased prevalence of this variant in affected individuals versus controls. The variant is observed in 115–905 population alleles in gnomAD, inconsistent with a highly penetrant rare disease variant.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No ClinGen-recognized expert panel or authoritative clinical practice guideline has classified NM_023110.3:c.1368G>T as pathogenic. Available ClinVar classifications are from single submitters without expert panel review.	clinvar
PM1	Not met	Although p.Met456Ile resides in the tyrosine kinase domain of FGFR1, the variant is not located in a statistically significant mutational hotspot per the hotspot screen. Without CSPEC/VCEP guidance identifying codon 456 as a critical functional domain for PM1, this criterion cannot be applied.
PM2	Met	The variant is present in gnomAD at low frequency — v2.1 AF 0.041% (115/280,958 alleles) and v4.1 AF 0.056% (905/1,614,218 alleles), both below the 0.1% threshold for PM2. However, the substantial carrier count (905 in v4.1) substantially weakens the evidence weight and this criterion should be considered borderline in the context of a rare disease gene.	gnomad_v2 gnomad_v4
PM5	Not met	Automated PM5 candidate harvesting found no same-residue (Met456) comparator variants with pathogenic or likely pathogenic classification in ClinVar. No manual comparator candidates were identified.	pm5_candidates clinvar
PM6	Not met	No de novo observation with unconfirmed parentage has been reported for this variant. No ClinVar submission or reviewed publication documents a de novo event.	clinvar
PP1	Not met	No family segregation data are available for NM_023110.3:c.1368G>T. No reviewed publication reports cosegregation of this variant with disease in affected family members.
PP2	Not met	FGFR1 has a mix of pathogenic and benign missense variants; it does not exhibit a low rate of benign missense variation that would support PP2. Without CSPEC/VCEP guidance defining a missense constraint metric for FGFR1, PP2 cannot be applied.	gnomad_v2 gnomad_v4
PP3	Not met	In silico predictions are discordant: REVEL score 0.802 suggests a damaging effect, but BayesDel score 0.069 predicts benign and SpliceAI delta 0.00 predicts no splicing impact. A single damaging prediction (REVEL) does not meet the 'multiple lines of computational evidence' threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype information is available in the case data. PP4 requires that the patient's phenotype or family history is highly specific for a disease associated with FGFR1, which cannot be assessed.
PP5	Not met	ClinVar reports a consensus classification of Likely benign/Benign from 10 of 11 clinical laboratories, with only 1 VUS. No reputable source classifies this variant as pathogenic. The ClinVar review status is 'criteria provided, single submitter' with no expert panel review.	clinvar
BA1	Not met	The maximum allele frequency in gnomAD is 0.056% (v4.1) with grpmax FAF of 0.069%, well below the 1% threshold required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency in gnomAD is 0.056% (v4.1) with grpmax FAF of 0.069%, below the 0.3% threshold for BS1. While the variant has 905 carriers in v4.1, the frequency does not formally exceed the BS1 cutoff of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous individuals are observed in gnomAD (v2.1 or v4.1). BS2 requires observation in a homozygous state in a healthy adult, which is not supported by available data.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate that p.Met456Ile has no deleterious effect. OncoKB lists the variant as 'Unknown Oncogenic Effect' with no functional data.	oncokb
BS4	Not met	No family segregation data are available to demonstrate lack of cosegregation with disease in affected family members.
BP1	Not met	FGFR1-related disorders are not solely caused by loss-of-function truncating variants; activating missense variants in the tyrosine kinase domain are a well-established pathogenic mechanism (e.g., craniosynostosis, Hartsfield syndrome, osteoglophonic dysplasia). BP1 requires that the disease mechanism is exclusively truncating, which is not the case for FGFR1.	pvs1_gene_context
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic dominant FGFR1 variant.
BP4	Not met	In silico predictions are discordant: REVEL 0.802 predicts damaging, while BayesDel 0.069 and SpliceAI 0.00 predict benign/neutral. BP4 requires multiple lines of computational evidence suggesting no impact, which is not met given the REVEL score in the damaging range.	revel bayesdel spliceai
BP5	Not met	No data are available indicating that this variant has been observed in a case with an alternative molecular cause for disease.
BP6	Met	Ten of eleven clinical laboratory submissions in ClinVar classify NM_023110.3:c.1368G>T as Likely benign (7 labs) or Benign (3 labs), with only one VUS. While no expert panel review is available, the strong inter-laboratory consensus towards benign supports BP6 at the supporting level.	clinvar
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; this is a single-nucleotide substitution.
BP7	N/A	NM_023110.3:c.1368G>T is a missense variant (p.Met456Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant in trans; no recessive inheritance model or trans data are provided for this case.
PM4	N/A	PM4 applies to non-frameshift indels altering protein length; this is a single-nucleotide missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.