NM_213647.2:c.1144G>T

FGFR4 · NP_998812.1:p.(Val382Leu) · NM_213647.2

GRCh37: chr5:176520225 G>T · GRCh38: chr5:177093224 G>T

Gene: FGFR4 Transcript: NM_213647.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

FGFR4

Transcript

NM_213647.2

Protein

NP_998812.1:p.(Val382Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting): Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant meeting the PM2 allele frequency threshold of <0.1%.

BP4 (supporting benign): Multiple lines of computational evidence predict a benign effect — REVEL 0.056, BayesDel -0.280588, and SpliceAI max delta 0.00.

PVS1, PS1-PS5, PM1, PM5-PM6, PP1-PP5, BA1, BS1-BS4, BP1-BP2, BP5-BP7 are not met or not applicable for this missense variant lacking variant-specific clinical, functional, or literature evidence.

Conflicting criteria (PM2 supporting pathogenic vs. BP4 supporting benign) result in a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 classification framework.

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	This is a missense variant (p.Val382Leu); does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per PMC6185798.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	No previously established pathogenic variant with the same amino acid change (p.Val382Leu) has been identified in ClinVar or the literature.	clinvar
PS2	N/A	No de novo data or parental testing information is available for this variant.
PS3	Not met	No variant-specific functional studies were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' and no experimental functional data for p.Val382Leu was found in the literature.	oncokb
PS4	N/A	No case-control or cohort studies comparing variant prevalence in affected vs. unaffected individuals are available.
PS5	N/A	This variant is absent from ClinVar and has no classification from a reputable source.	clinvar
PM1	Not met	Position 382 is not in a statistically significant cancer hotspot (cancerhotspots.org negative). Although FGFR4 contains well-characterized functional domains including an intracellular tyrosine kinase domain, no literature evidence establishes residue 382 (located in the extracellular region) as lying within a critical functional domain where missense variants are an established disease mechanism.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), consistent with a rare variant meeting the PM2 allele frequency threshold of <0.1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No other pathogenic missense variants at the same residue (p.Val382) were identified in ClinVar; PM5 candidate harvesting returned zero same-residue comparators.	pm5_candidates clinvar
PM6	N/A	No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant.
PP1	N/A	No family segregation data are available for this variant.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation and a high proportion of pathogenic missense variants. HCI prior data is not available for FGFR4, and no gnomAD constraint metrics (Z-score, pLI, missense o/e) have been provided to support a low benign missense tolerance for this gene.
PP3	Not met	Multiple in silico predictors support a benign effect: REVEL score 0.056 (strongly benign, well below 0.5 threshold), BayesDel score -0.280588 (negative/benign), and SpliceAI max delta 0.00 (no predicted splicing impact). No computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	N/A	No patient phenotype information is available to assess whether the clinical presentation is specific for FGFR4-related disease.
PP5	N/A	This variant is absent from ClinVar; no reputable source has classified it as pathogenic. ClinVar absence precludes PP5 application at any strength.	clinvar
BA1	Not met	This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0.0%, well below the BA1 threshold of >1.0%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0.0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	This variant is absent from gnomAD population databases and has not been observed in any healthy adult individual, homozygous or heterozygous.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a benign effect for p.Val382Leu have been identified. The absence of functional data does not constitute evidence of a benign effect.
BS4	N/A	No family segregation data are available to assess lack of segregation with disease.
BP1	Not met	FGFR4 is a receptor tyrosine kinase in the FGFR family. Established germline FGFR family disease mechanisms are predominantly gain-of-function missense mutations (e.g., FGFR2 in Apert syndrome, FGFR3 in achondroplasia), not primarily truncating variants. BP1 requires a gene where truncating variants are the primary disease mechanism, which is not the case for FGFR4.
BP2	N/A	No observation of this variant in trans with a known pathogenic variant is available.
BP4	Met	Multiple lines of computational evidence suggest this variant has no deleterious impact: REVEL score 0.056 (strongly benign, well below 0.5), BayesDel score -0.280588 (benign), and SpliceAI max delta 0.00 (no predicted splicing alteration). Three independent in silico tools consistently predict a benign effect.	revel bayesdel spliceai
BP5	N/A	No alternate molecular basis for disease has been identified in this case.
BP6	N/A	This variant is absent from ClinVar; no reputable source has classified it as benign. ClinVar absence precludes BP6 application.	clinvar
BP7	N/A	c.1144G>T is a missense variant (p.Val382Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact, or intronic variants outside conserved splice sites.
BP3	N/A	Variant is a missense substitution; BP3 applies only to in-frame insertions/deletions in non-repeat regions.
PM3	N/A	Variant is absent from population databases and has not been observed in trans with a known pathogenic variant.
PM4	N/A	Variant is a missense substitution; PM4 applies only to non-repeat-region stop-loss, in-frame deletions/insertions, or single-amino-acid deletions.

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