FGFR4

Final classification

Benign

FGFR4 c.1162G>A · p.Gly388Arg

FGFR4

Gene

FGFR4

Transcript

NM_213647.2

HGVS · transcript:coding

NM_213647.2:c.1162G>A

Consequence

N/A

GRCh38

chr5:177093242 G>A

GRCh37

chr5:176520243 G>A

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: BA1 stand-alone benign, BS1 strong benign, BS2 strong benign, BP1 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 1 stand-alone benign + 2 strong benign + 3 supporting benign, which maps to Benign. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BS2 strong benign, BP1 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 1 stand-alone benign + 2 strong benign + 3 supporting benign, which maps to Benign.

Classification rationale

BA1BS1BS2BP1BP4BP6 Benign

FGFR4 c.1162G>A

FGFR4 c.1162G>A (p.Gly388Arg) is an extremely common polymorphism with a global allele frequency of 32.1% in gnomAD v2.1 (89,487/278,670 alleles, 15,309 homozygotes) and 30.3% in gnomAD v4.1 (487,943/1,612,462 alleles, 76,363 homozygotes), meeting BA1 (stand-alone benign).¹ The variant frequency far exceeds the threshold for any rare monogenic disorder (BS1 threshold >0.3%), with the highest subpopulation frequency of 45.1% in East Asians.² The variant has been observed in the homozygous state in 15,309 individuals in gnomAD v2.1, consistent with Hardy-Weinberg equilibrium for a common benign polymorphism and incompatible with a fully penetrant pathogenic variant (BS2).³ FGFR4 germline disease is associated with loss-of-function; this is a missense variant not expected to recapitulate the LoF disease mechanism (BP1).⁴ Multiple in silico predictors are consistent with a benign interpretation: BayesDel score 0.0305 (benign), REVEL 0.519 (neutral), and SpliceAI max delta 0.02 (no splicing impact) (BP4).⁵ ClinVar classifies this variant as Benign based on submissions from 3 clinical laboratories (ClinVar VariationID 16326) (BP6).⁶ Functional studies demonstrate FGFR4 G388R has gain-of-function effects (STAT3 binding, increased cancer cell motility) in cancer models, but these do not establish pathogenicity for a monogenic germline disorder and are superseded by the overwhelming population frequency evidence.⁷

BA1 + BS1 + BS2 + BP1 + BP4 + BP6 → Benign

1 gnomad_v2 ↗gnomad_v4 ↗

2 gnomad_v2 ↗

3 gnomad_v2 ↗

4 pvs1_gene_context

5 revelbayesdelspliceai ↗

6 clinvar ↗

7 PMID:11830541 ↗PMID:26675719 ↗

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

FGFR4 NM_213647.2

Fetching transcript structure from UCSC…

Applied criteria · 6 applied · 9 assessed

Applied · 6

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

Extremely high population frequency: gnomAD v2.1 AF=32.1% (89,487/278,670 alleles, 15,309 homozygotes) and gnomAD v4.1 AF=30.3% (487,943/1,612,462 alleles, 76,363 homozygotes). Far exceeds the BA1 threshold of >1%.

gnomAD v2.1: 89487/278670 alleles

gnomad_v2 ↗gnomad_v4 ↗

✓

BS1 strong Benign

Variant frequency (gnomAD AF=32.1%) far exceeds the threshold for any rare monogenic disorder (BS1 threshold >0.3%), and is inconsistent with a highly penetrant pathogenic role.

Global AF=32.1% (v2.1) and 30.3% (v4.1)orders of magnitude above the BS1 threshold of >0.3%.Observed across all major population groups with AF ranging from 12.9% (African) to 45.1% (East Asian).

gnomad_v2 ↗gnomad_v4 ↗

✓

BS2 strong Benign

Observed in homozygous state in 15,309 individuals in gnomAD v2.1 (76,363 in v4.1), demonstrating the variant is compatible with normal development and inconsistent with a fully penetrant pathogenic variant causing a severe monogenic disorder.

gnomAD v2.1: 15309 homozygotes observed.gnomAD v4.1: 76

gnomad_v2 ↗gnomad_v4 ↗

✓

BP1 supporting Benign

Missense variant in FGFR4, a gene for which loss-of-function is the documented disease mechanism in germline FGFR4-related disorders (familial pituitary adenomas). Truncating variants, not missense changes, are the primarily established pathogenic variant type.

FGFR4 germline disease mechanism is loss-of-function (supported by PMID:26186299 and other sources).Missense variants in a primarily LoF disease gene are less likely to be pathogenic.

✓

BP4 supporting Benign

Multiple in silico predictors suggest no deleterious impact: BayesDel score=0.0305 (benign), REVEL=0.519 (borderline/neutral), SpliceAI max delta=0.02 (no splicing impact).

BayesDel: 0.0305 (strongly benign).REVEL: 0.519 (neutralwell below pathogenic threshold of ~0.75).

spliceai ↗

✓

BP6 supporting Benign

ClinVar classifies this variant as Benign based on submissions from 3 clinical laboratories (ClinVar VariationID 16326).

ClinVar VariationID 16326: Benign classificationcriteria provided (single submitter tier).3 clinical laboratories independently classify as Benign.

clinvar ↗

Assessed · not applied

Pathogenic

PS1 No alternative nucleotide change at codon 388 resulting in the same amino acid substitution (p.Gly388Arg) has been reported as pathogenic in ClinVar.

PS3 Functional studies demonstrate that FGFR4 p.Gly388Arg alters receptor biology (STAT3 binding site exposure, increased cancer cell motility), but these are gain-of-function effects in cancer models rather than evidence of a deleterious effect causing a monogenic germline disorder.

PS4 No case-control data comparing affected versus unaffected individuals for a specific FGFR4-related monogenic germline disorder are available.

PM1 The variant lies in the transmembrane domain of FGFR4 but is not located in a statistically significant mutational hotspot (cancerhotspots.org: not significant).

PM2 Variant is extremely common in population databases (gnomAD v2.1 AF=32.1%, v4.1 AF=30.3%), far exceeding the PM2 threshold of <0.1%.

PP2 FGFR4 does not have a low rate of benign missense variation; this variant itself is a common polymorphism present in over 30% of the general population.

PP3 Multiple in silico predictors do not support a deleterious effect: BayesDel score=0.0305 (benign), REVEL=0.519 (borderline/neutral), SpliceAI max delta=0.02 (no splicing impact).

PP5 ClinVar consensus is Benign (3 clinical laboratories).

Benign

BS3 Published functional studies (PMID:11830541, PMID:26675719) demonstrate that FGFR4 p.Gly388Arg has biological activity (STAT3 binding, altered cancer cell motility) rather than no effect.

N/A · 11 PVS1 · PS2 · PM5 · PM6 · PP1 · PP4 · BS4 · BP2 · BP3 · BP5 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.302607; MAF= 30.26074%, 487943/1612462 alleles, homozygotes = 76363) and has highest observed frequency in the East Asian population (AF= 0.438296; MAF= 43.82956%, 19626/44778 alleles, homozygotes = 4303); grpmax FAF= 0.433162.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.321122; MAF= 32.11218%, 89487/278670 alleles, homozygotes = 15309) and has highest observed frequency in the East Asian population (AF= 0.450672; MAF= 45.06722%, 8917/19786 alleles, homozygotes = 2008); grpmax FAF= 0.441438.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.3066724625081504, 5644/18404 alleles, homozygotes = 883).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

30% · 487943 / 1,612,462
76363 hom · FAF 43%

East Asian 19626 / 44,778	44% 4303 hom
Admixed American 23199 / 59,888	39% 4684 hom
South Asian 31927 / 91,004	35% 5806 hom
European (Finnish) 20954 / 63,772	33% 3513 hom
Ashkenazi Jewish 9351 / 29,532	32% 1477 hom
Remaining individuals 19204 / 62,440	31% 3037 hom
European (non-Finnish) 351873 / 1,179,108	30% 52564 hom
Middle Eastern 1740 / 6,050	29% 267 hom
Amish 248 / 912	27% 32 hom
African/African American 9821 / 74,978	13% 680 hom

gnomAD v2.1

32% · 89487 / 278,670
15309 hom · FAF 44%

East Asian 8917 / 19,786	45% 2008 hom
Admixed American 14782 / 35,216	42% 3124 hom
South Asian 10745 / 30,522	35% 1929 hom
European (Finnish) 8097 / 24,858	33% 1399 hom
Ashkenazi Jewish 3254 / 10,218	32% 512 hom
Remaining individuals 2261 / 7,124	32% 349 hom
European (non-Finnish) 38234 / 126,270	30% 5780 hom
African/African American 3197 / 24,676	13% 208 hom

gnomAD Canada 🇨🇦

31% · 5644 / 18,404
883 hom · FAF 44%

indel · split

East Asian 636 / 1,338	48% 150 hom
South Asian 495 / 1,360	36% 87 hom
Latino/Admixed American 286 / 836	34% 48 hom
Ashkenazi Jewish 256 / 832	31% 36 hom
Remaining individuals 343 / 1,138	30% 54 hom
European (non-Finnish) 3474 / 11,730	30% 498 hom
Middle Eastern 31 / 142	22% 1 hom
European (Finnish) 1 / 8	12%
African/African American 122 / 1,020	12% 9 hom

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 16326)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.519. BayesDel score = 0.0304758.

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 previously been reported in somatic cancers (COSMIC; COSV52800825, n = 88 times).

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

Triaged references · 4 PMIDs not cited in assessment

11830541 ↗ Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26675719 ↗ Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site. CLINVAR

33116287 ↗ High-depth African genomes inform human migration and health. CLINVAR