NM_213647.2:c.770C>T

FGFR4 · NP_998812.1:p.(Ala257Val) · NM_213647.2

GRCh37: chr5:176519364 C>T · GRCh38: chr5:177092363 C>T

Gene: FGFR4 Transcript: NM_213647.2

Final call

VUS

PM2 supporting

Variant details

Gene

FGFR4

Transcript

NM_213647.2

Protein

NP_998812.1:p.(Ala257Val)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent from gnomAD v2.1 and gnomAD-Canada v1.0, with 0/1,601,818 alleles and zero homozygotes in gnomAD v4.1.

Overall: VUS - a single supporting-strength criterion (PM2) does not satisfy any ACMG/AMP 2015 Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

Final determination: Generic ACMG/AMP 2015 fallback: 1 PM2 (supporting) alone does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, 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	Not applicable: c.770C>T is a missense substitution, so no null-variant mechanism (nonsense-mediated decay, truncation, splice disruption) applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: the variant is absent from ClinVar, and no comparator data on a pathogenic change producing the identical amino acid was available.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, parentage confirmation, or de novo testing result is available.
PS3	Not assessed	Not assessed: no validated functional or biochemical assay data (kinase activity, phosphorylation, proliferation) for p.Ala257Val was available.
PS4	Not assessed	Not assessed: no affected-case series or case-control dataset reports this exact FGFR4 variant.
PM1	Not met	Not met: cancerhotspots.org returned no significant-hotspot row for FGFR4 A257, and no residue-level functional-domain annotation places codon 257 in a critical domain.
PM2	Met	Met (supporting): absent from gnomAD v2.1 and gnomAD-Canada v1.0, with 0/1,601,818 alleles and zero homozygotes in gnomAD v4.1.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observation, second variant, phase result, or recessive FGFR4 disease evidence is present.	final_classification_framework generic_acmg_combination_rules
PM4	N/A	Not applicable: missense substitution causes no protein length change, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no previously established pathogenic variant with a different amino acid substitution at residue 257 was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no report identifies the variant as de novo without confirmed parentage.
PP1	Not assessed	Not assessed: no affected relatives, genotypes, phenotypes, or informative meioses are reported.
PP2	Not assessed	Not assessed: no missense-constraint metric (e.g., gnomAD Z-score) or established missense disease mechanism for FGFR4 was available.
PP3	Not met	Not met: REVEL score 0.396 falls in the gray zone (0.250-0.750), below the >0.750 PP3 supporting threshold.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-specificity evidence is supplied.
PP5	Not met	Not met: no exact-variant ClinVar record or expert-panel Pathogenic/Likely pathogenic assertion is present.	clinvar
BA1	Not met	Not met: 0/1,601,818 alleles in gnomAD v4.1 (AF 0) does not show a stand-alone benign population frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no observed alleles in gnomAD v4.1, v2.1, or gnomAD-Canada v1.0, so frequency cannot exceed a disease-compatible threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observed gnomAD homozygotes or phenotype-verified healthy adult carriers are available.	gnomad_v4
BS3	Not assessed	Not assessed: no functional or biochemical assay data showing normal activity for p.Ala257Val was available.
BS4	Not assessed	Not assessed: no family data show lack of segregation between the variant and a relevant phenotype.
BP1	Not assessed	Not assessed: no formal gene-level curation of the missense-versus-truncating disease mechanism for FGFR4 was available.
BP2	Not assessed	Not assessed: no co-occurrence with a pathogenic variant, phase information, or established dominant FGFR4 disease context is available.	final_classification_framework generic_acmg_combination_rules
BP3	N/A	Not applicable: missense substitution does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.396 is above the <0.250 BP4 supporting threshold.	revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level molecular results or established alternative genetic cause are supplied.
BP6	Not met	Not met: no exact-variant ClinVar record or expert-panel Benign/Likely benign assertion is present.	clinvar
BP7	N/A	Not applicable: the variant is missense, not synonymous, so BP7's silent-variant premise does not hold.	generic_acmg_combination_rules

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.