NM_213647.2:c.317C>T

FGFR4 · NP_998812.1:p.(Ser106Phe) · NM_213647.2

GRCh37: chr5:176517616 C>T · GRCh38: chr5:177090615 C>T

Gene: FGFR4 Transcript: NM_213647.2

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

FGFR4

Transcript

NM_213647.2

Protein

NP_998812.1:p.(Ser106Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_213647.2:c.317C>T (p.Ser106Phe) is absent from all queried population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at moderate strength.

Multiple in silico predictors suggest no significant impact on the gene product: BayesDel score is -0.025 (benign range), SpliceAI max delta is 0.00, and REVEL score of 0.43 falls below standard pathogenicity thresholds, meeting BP4 at supporting benign strength.

The variant is absent from ClinVar and the literature; no functional, segregation, de novo, case-control, or clinical classification data are available to assess PS1–PS5, PM6, PP1–PP5, BS2–BS4, BP2, BP5, or BP6.

PVS1 is not applicable: c.317C>T is a missense variant encoding p.Ser106Phe and does not fall into any null-variant bucket under the ClinGen SVI PVS1 decision tree (PMC6185798).

PM1 is not met: residue 106 is not a statistically significant mutational hotspot and FGFR4 lacks a germline disease-associated hotspot map.

PM5 is not applicable: no same-residue pathogenic comparator variant at codon 106 with a different amino acid change was identified in ClinVar.

BP1 is not met: while FGFR4 loss-of-function is supported as a disease mechanism by gene-level literature, the gene-disease validity has not been established at a ClinGen level and missense variants are not excluded as a disease mechanism.

The evidence profile consists of one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), resulting in conflicting evidence. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this 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	NM_213647.2:c.317C>T is a missense variant (p.Ser106Phe) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No alternate nucleotide change producing the same amino acid substitution (p.Ser106Phe) has been identified as pathogenic in ClinVar or the literature. Without a known pathogenic comparator arising from a different nucleotide change at the same codon, PS1 cannot be assessed.
PS2	Not assessed	No de novo observation for NM_213647.2:c.317C>T was identified. Neither ClinVar submissions nor the literature report a confirmed de novo occurrence with parental testing.
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for NM_213647.2:c.317C>T (p.Ser106Phe). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. COSMIC has no entries for this variant.
PS4	Not assessed	No case-control or statistical enrichment data are available for NM_213647.2:c.317C>T. The variant is absent from ClinVar and the literature, precluding any assessment of prevalence in affected individuals versus controls.
PS5	Not assessed	No familial segregation data are available for NM_213647.2:c.317C>T. No pedigrees or segregation analyses have been reported in ClinVar or the literature.
PM1	Not met	NM_213647.2:c.317C>T (p.Ser106Phe) is located in the extracellular immunoglobulin-like domain of FGFR4, but does not lie in a statistically significant mutational hotspot per cancerhotspots.org, and no germline disease-associated mutational hotspot encompassing codon 106 has been established for FGFR4.
PM2	Met	NM_213647.2:c.317C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency < 0.1%), meeting the PM2 criterion for a variant absent or at extremely low frequency in large population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variant at codon 106 with a different amino acid change and a pathogenic classification was identified in ClinVar. The automatic PM5 candidate search found zero candidate variants at this residue.	pm5_candidates
PM6	Not assessed	No de novo observation with confirmed maternity and paternity was identified for NM_213647.2:c.317C>T. Neither ClinVar nor the literature report a de novo occurrence meeting PM6 requirements.
PP1	Not assessed	No co-segregation data are available for NM_213647.2:c.317C>T. No family studies linking this variant to disease have been reported.
PP2	Not assessed	HCI prior scores are unavailable for FGFR4, and no gene-level missense constraint metric (e.g., missense Z-score) is available from the evidence pipeline. FGFR4 has not been established as a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3	Not met	In silico predictors do not provide multiple lines of evidence supporting a deleterious effect. REVEL score is 0.43 (below typical pathogenicity threshold of 0.5), BayesDel is -0.025 (benign-leaning), and SpliceAI max delta is 0.00 (no predicted splice impact). These results do not meet the threshold for PP3.	revel bayesdel spliceai
PP4	Not assessed	No proband phenotype or clinical data are available for NM_213647.2:c.317C>T. The variant is novel with no associated clinical submissions in ClinVar.
PP5	Not assessed	NM_213647.2:c.317C>T is absent from ClinVar and has not been classified by any reputable clinical laboratory or expert panel. No source credibly reports this variant as pathogenic.
BA1	Not met	NM_213647.2:c.317C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_213647.2:c.317C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of NM_213647.2:c.317C>T in healthy adults. The variant is absent from population databases, so BS2 (observed in a healthy adult for a fully penetrant disorder) cannot be evaluated without individual-level data.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of NM_213647.2:c.317C>T (p.Ser106Phe) were identified. OncoKB reports no variant-specific functional evidence.
BS4	Not assessed	No segregation data are available to evaluate lack of segregation with disease. No family studies for NM_213647.2:c.317C>T have been reported.
BP1	Not met	Although FGFR4 loss-of-function is supported as a disease mechanism by targeted literature review (PMID:26186299, PMID:29735309, PMID:36973520, PMID:19863427, PMID:23880303), there is insufficient evidence that FGFR4-associated disease is caused exclusively by truncating variants such that BP1 would apply to a missense variant. The gene-disease validity has not been established at a ClinGen level.	pvs1_gene_context
BP2	Not assessed	No data are available regarding observation of NM_213647.2:c.317C>T in trans with a pathogenic dominant variant. The variant is absent from ClinVar and literature, precluding assessment of allelic configuration.
BP4	Met	Multiple lines of in silico evidence suggest no significant impact on gene product. BayesDel score is -0.025 (benign range), SpliceAI max delta is 0.00 (no predicted splice alteration), and REVEL score is 0.43 (below accepted pathogenicity thresholds). Together these predictors favor a neutral or minimally disruptive effect.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding observation of NM_213647.2:c.317C>T in a case with an alternative molecular cause for disease. The variant is absent from ClinVar and literature.
BP6	Not assessed	NM_213647.2:c.317C>T is absent from ClinVar and has not been classified as benign by any reputable source. No BP6 assessment is possible.
BP7	N/A	NM_213647.2:c.317C>T is a missense variant (p.Ser106Phe), not a synonymous or intronic variant. BP7 applies only to synonymous variants for which splicing prediction algorithms predict no impact.
BP3	N/A	NM_213647.2:c.317C>T is a single-nucleotide substitution, not an in-frame deletion or insertion. BP3 is reserved for in-frame indels in repetitive regions.
PM3	N/A	FGFR4 germline disease association and inheritance pattern are not established at a ClinGen level. PM3 (detected in trans with a pathogenic variant for recessive disorders) cannot be applied without a confirmed recessive inheritance model.
PM4	N/A	NM_213647.2:c.317C>T is a missense substitution, not an in-frame deletion or insertion. PM4 is reserved for protein length changes due to in-frame indels or stop-loss variants.

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