NM_213647.2:c.25G>A

FGFR4 · NP_998812.1:p.(Gly9Arg) · NM_213647.2

GRCh37: chr5:176516628 G>A · GRCh38: chr5:177089627 G>A

Gene: FGFR4 Transcript: NM_213647.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FGFR4

Transcript

NM_213647.2

Protein

NP_998812.1:p.(Gly9Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting): This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.

BP4 (supporting): Multiple computational predictors — REVEL (0.39), BayesDel (-0.119), and SpliceAI (max delta 0.00) — concordantly suggest no deleterious impact on the gene product.

PVS1 is not applicable as this is a missense variant (p.Gly9Arg) and does not qualify as a null variant under the ClinGen SVI PVS1 framework.

No CSPEC/VCEP framework exists for FGFR4; classification follows generic ACMG/AMP 2015 combination rules (Richards et al. 2015, PMID:25741868).

Under generic ACMG/AMP 2015 rules, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) do not meet any classification threshold. This variant is classified as a Variant of Uncertain Significance (VUS).

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	PVS1 is not applicable: NM_213647.2:c.25G>A is a missense variant (p.Gly9Arg) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants as defined by the ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	Insufficient evidence: no known pathogenic variant with the same amino acid change (p.Gly9Arg) has been identified in ClinVar or the literature. A comparator pathogenic variant at this residue is required for PS1.	clinvar
PS2	Not assessed	No de novo data are available for this variant. PS2 requires confirmed de novo occurrence with both parental samples tested and maternity/paternity confirmed.
PS3	Not assessed	No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no reviewed functional evidence. PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect.	oncokb
PS4	Not assessed	No case-control data are available to assess whether the variant has significantly increased prevalence in affected individuals versus controls.
PS5	Not assessed	This variant has no ClinVar submissions and has not been reported as pathogenic by a reputable source with independent evidence. PS5 is reserved for variants recently described as pathogenic with evidence not yet independently verified.	clinvar
PM1	Not met	This variant (p.Gly9Arg at residue 9) does not lie in a statistically significant mutational hotspot as assessed by CancerHotspots.org, nor is it located in a well-characterized critical functional domain with established pathogenic enrichment for FGFR4.
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of allele frequency <0.1% in large population databases for a gene without a CSPEC/VCEP population frequency framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No known pathogenic missense variant at the same residue (Gly9) with a different amino acid change was identified in ClinVar or the literature. PM5 requires a comparator pathogenic missense variant at the same codon.	pm5_candidates clinvar
PM6	Not assessed	No de novo data are available. PM6 requires a de novo observation with maternity/paternity confirmed, with the variant being absent in both biological parents.
PP1	Not assessed	No cosegregation data are available. PP1 requires evidence of cosegregation with disease in multiple affected family members.
PP2	Not assessed	HCI prior probability data are unavailable for FGFR4. PP2 requires a low rate of benign missense variation in the gene coupled with a high proportion of pathogenic missense variants, which cannot be assessed without HCI prior scores.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.39 (below the pathogenic threshold of 0.5, in the indeterminate range), BayesDel score is -0.119 (negative, supporting a benign prediction), and SpliceAI predicts no splicing impact (max delta score = 0.00). PP3 requires multiple computational predictors to concordantly support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No phenotype or family history data specific to this variant are available. PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not assessed	This variant has not been classified as pathogenic by any reputable clinical laboratory or expert panel. PP5 requires a prior pathogenic classification from a source whose evidence has not been independently reviewed.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency greater than 1% in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD across all populations. BS1 requires an allele frequency greater than expected for the disorder (>0.3% under generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adult individuals with complete ascertainment. BS2 requires the variant to be observed in a healthy adult individual for a fully penetrant dominant disorder.
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect were identified. BS3 requires functional assays that convincingly show the variant does not impair protein function.
BS4	Not assessed	No segregation data are available to evaluate nonsegregation with disease. BS4 requires lack of segregation in affected family members.
BP1	N/A	FGFR4 disease mechanisms include gain-of-function missense variants (as a receptor tyrosine kinase implicated in cancer via mutation, amplification, and rearrangement). BP1 is intended for genes in which only truncating variants cause disease, which does not apply to FGFR4.
BP2	Not assessed	No data are available regarding observation in trans with a pathogenic variant. BP2 requires the variant to be observed in trans with a pathogenic variant for a fully penetrant recessive disorder; the FGFR4 disease spectrum does not clearly follow a recessive inheritance pattern.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.39 (below the pathogenic threshold of 0.5), BayesDel score is -0.119 (negative, in the benign range), and SpliceAI predicts no splicing impact (max delta = 0.00). Multiple in silico predictors concordantly support a benign effect.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternative molecular cause for the phenotype. BP5 requires that the variant be found in a case with an alternative molecular basis for disease.
BP6	Not assessed	This variant has not been classified as benign by a reputable source. BP6 requires a prior benign classification from a reputable clinical laboratory or database.	clinvar
BP7	N/A	NM_213647.2:c.25G>A is a missense variant (p.Gly9Arg), not a synonymous variant. BP7 only applies to synonymous variants with no predicted splicing impact.
BP3	N/A	Skipped per workflow instruction: not assessed for this case.
PM3	N/A	Skipped per workflow instruction: not assessed for this case.
PM4	N/A	Skipped per workflow instruction: not assessed for this case.

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