Variant classification summary

NM_213647.2:c.1162G>A

FGFR4 · NP_998812.1:p.(Gly388Arg) · NM_213647.2

GRCh37: chr5:176520243 G>A · GRCh38: chr5:177093242 G>A

Gene: FGFR4 Transcript: NM_213647.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP1 supporting benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

FGFR4

Transcript

NM_213647.2

Protein

NP_998812.1:p.(Gly388Arg)

gnomAD AF

0.30260744129163974 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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.

3

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).

4

FGFR4 germline disease is associated with loss-of-function; this is a missense variant not expected to recapitulate the LoF disease mechanism (BP1).

5

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).

6

ClinVar classifies this variant as Benign based on submissions from 3 clinical laboratories (ClinVar VariationID 16326) (BP6).

7

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cell motility) in cancer models, but these do not establish pathogenicity for a monogenic germline disorder and are superseded by the overwhelming population frequency evidence.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	Missense variant (p.Gly388Arg); does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus variants).	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change at codon 388 resulting in the same amino acid substitution (p.Gly388Arg) has been reported as pathogenic in ClinVar.	clinvar
PS2	N/A	No de novo data available for this variant.
PS3	Not met	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. The variant is an established common polymorphism (gnomAD AF >30%).	PMID:11830541 PMID:26675719
PS4	Not met	No case-control data comparing affected versus unaffected individuals for a specific FGFR4-related monogenic germline disorder are available.
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 framework used for this classification.
PM1	Not met	The variant lies in the transmembrane domain of FGFR4 but is not located in a statistically significant mutational hotspot (cancerhotspots.org: not significant). The extremely high population frequency (gnomAD AF >30%) is inconsistent with a pathogenic mutational hotspot.	gnomad_v2 gnomad_v4
PM2	Not met	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%.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic missense variants at codon 388 were identified in ClinVar; PM5 candidate search returned no comparator variants.	pm5_candidates clinvar
PM6	N/A	No de novo data available for this variant.
PP1	N/A	No segregation data available.
PP2	Not met	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.	gnomad_v2 gnomad_v4
PP3	Not met	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).	revel bayesdel spliceai
PP4	N/A	No patient phenotype or clinical data available.
PP5	Not met	ClinVar consensus is Benign (3 clinical laboratories). The OMIM submission (SCV000038000) classifying the variant as Pathogenic is flagged as literature-only with no assertion criteria and is contradicted by current clinical consensus.	clinvar
BA1	Met	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 gnomad_v4
BS1	Met	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.	gnomad_v2 gnomad_v4
BS2	Met	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 gnomad_v4
BS3	Not met	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. Evidence of a gain-of-function alteration does not constitute evidence of no damaging effect for BS3.	PMID:11830541 PMID:26675719
BS4	N/A	No segregation data available.
BP1	Met	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.	pvs1_gene_context
BP2	N/A	No data on observation in trans with a known pathogenic variant.
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion in a repetitive region.
BP4	Met	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).	revel bayesdel spliceai
BP5	N/A	No data on observation in cases with an alternate molecular basis for disease.
BP6	Met	ClinVar classifies this variant as Benign based on submissions from 3 clinical laboratories (ClinVar VariationID 16326).	clinvar
BP7	N/A	Missense variant (p.Gly388Arg), not a synonymous variant.

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