FGFR4

Final classification

VUS

FGFR4 c.1144G>T · p.Val382Leu

FGFR4

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%.

Gene

FGFR4

Transcript

NM_213647.2

HGVS · transcript:coding

NM_213647.2:c.1144G>T

Consequence

N/A

GRCh38

chr5:177093224 G>T

GRCh37

chr5:176520225 G>T

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

Classification rationale

PM2 BP4 VUS

FGFR4 c.1144G>T

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%.¹ BP4 (supporting benign): Multiple lines of computational evidence predict a benign effect — REVEL 0.056, BayesDel -0.280588, and SpliceAI max delta 0.00.² 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.³ 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.⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗oncokb ↗pm5_candidates

4 generic_acmg_combination_rules

Gene diagram · NM_213647.2 · variants mapped to exon structure

FGFR4 NM_213647.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 9 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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 v2.1: absent (AF = 0.0)gnomAD v4.1: absent (AF = 0.0)gnomAD-Canada v1.0: absent (AF = 0.0)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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: 0.056 (benignthreshold ≥0.5 for damaging)BayesDel: -0.280588 (benign

spliceai ↗

Assessed · not applied

Pathogenic

PS3 No variant-specific functional studies were identified.

PM1 Position 382 is not in a statistically significant cancer hotspot (cancerhotspots.org negative).

PP2 PP2 requires a gene with a low rate of benign missense variation and a high proportion of pathogenic missense variants.

PP3 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).

Benign

BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada).

BS1 This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada).

BS2 This variant is absent from gnomAD population databases and has not been observed in any healthy adult individual, homozygous or heterozygous.

BS3 No functional studies demonstrating a benign effect for p.Val382Leu have been identified.

BP1 FGFR4 is a receptor tyrosine kinase in the FGFR family.

N/A · 17 PVS1 · PS1 · PS2 · PS4 · PM3 · PM4 · PM5 · PM6 · PP1 · PP4 · PP5 · BS4 · BP2 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.056. BayesDel score = -0.280588.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR4, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification at low frequencies in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots