Variant classification summary

NM_000142.4:c.1267G>A

FGFR3 · NP_000133.1:p.(Val423Met) · NM_000142.4

GRCh37: chr4:1806551 G>A · GRCh38: chr4:1804824 G>A

Gene: FGFR3 Transcript: NM_000142.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FGFR3

Transcript

NM_000142.4

Protein

NP_000133.1:p.(Val423Met)

gnomAD AF

6.452903483922591e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000142.4:c.1267G>A (p.Val423Met) is a missense variant in FGFR3, a receptor tyrosine kinase in which gain-of-function missense variants cause skeletal dysplasias including achondroplasia.

2

This variant is extremely rare in population databases, observed in only 1 of 1,549,690 alleles (AF=6.45×10⁻⁷) in gnomAD v4.1 and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting strength.

3

Multiple in silico tools (BayesDel 0.157, SpliceAI max delta 0.0) predict no significant impact on gene product or splicing, meeting BP4 at supporting strength.

4

The variant is absent from ClinVar and has not been reported in the medical literature. No functional studies, case-control data, cosegregation data, or de novo reports are available.

5

The net evidence profile is indeterminate: one supporting pathogenic criterion (PM2_supporting) and one supporting benign criterion (BP4_supporting) yielding a net classification of Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.

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	This is a missense variant (c.1267G>A, p.Val423Met). PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus); the ClinGen SVI PVS1 framework (PMC6185798) confirms this variant falls into the 'other' bucket with no default PVS1 strength.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No different nucleotide change at the same codon (c.1267) has been identified as pathogenic. The variant is absent from ClinVar, and no literature reports an alternate pathogenic substitution at this position.	clinvar
PS2	Not assessed	De novo confirmation requires parental genotype data demonstrating the variant arose de novo. No family studies, trio sequencing, or de novo reports are available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies have been identified for NM_000142.4:c.1267G>A (p.Val423Met). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control data demonstrate increased prevalence in affected individuals versus controls. The variant is absent from ClinVar and is observed in only 1 of 1,549,690 alleles in gnomAD v4.1, providing no statistical evidence of disease association.	gnomad_v4 clinvar
PS5	Not assessed	No established pathogenic classification from a reputable source with supporting functional (PS3) and prevalence (PS4) evidence is available for this variant.
PM1	Not met	This variant is not located in a statistically significant mutational hotspot. Although residue V423 lies in the tyrosine kinase domain of FGFR3, it is not an established FGFR3 pathogenic hotspot residue and the domain contains benign missense variation.
PM2	Met	This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada, and is observed with an allele frequency of 6.45×10⁻⁷ (1/1,549,690 alleles) in gnomAD v4.1, well below the PM2 threshold of 0.1%. This supports PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variants were identified. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics, and no alternate pathogenic missense at codon 423 has been reported.	pm5_candidates
PM6	Not assessed	No de novo occurrence has been reported for this variant. PM6 requires confirmation that the variant arose de novo with confirmed maternity and paternity.
PP1	Not assessed	No cosegregation data are available for this variant. PP1 requires demonstration of segregation with disease in multiple affected family members.
PP2	Not assessed	PP2 requires gene-level missense constraint metrics (e.g., missense Z-score) demonstrating a low rate of benign missense variation. Such gene-level constraint data are not available in the evidence packet for FGFR3.
PP3	Not met	In silico predictions are discordant. REVEL (0.566) favors pathogenicity, but BayesDel (0.157) is benign-leaning. SpliceAI predicts no splicing impact (max delta 0.0). A single pathogenic prediction does not constitute 'multiple lines of computational evidence supporting a deleterious effect' as required by PP3.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical information is available for PP4 assessment. PP4 requires that the variant was identified in a patient whose phenotype or family history is highly specific for the disease.
PP5	Not assessed	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar, and no clinical laboratory or expert panel classification is available.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in population databases. The maximum observed allele frequency for this variant is 1.19×10⁻⁵ (0.00119%) in the South Asian subpopulation of gnomAD v4.1, far below the 1% threshold.	gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in population databases. The maximum observed allele frequency for this variant is 1.19×10⁻⁵ (0.00119%) in the South Asian subpopulation of gnomAD v4.1, far below the 0.3% threshold.	gnomad_v4
BS2	Not met	BS2 requires observation in a homozygous state in healthy adults or at a frequency inconsistent with disease penetrance. This variant has zero homozygotes in gnomAD v4.1 (1 allele total) and is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing are available for this variant.
BS4	Not met	BS4 requires lack of segregation in affected family members. No family segregation studies are available to evaluate this criterion.
BP1	Not met	BP1 requires a missense variant in a gene where primarily truncating variants cause disease. FGFR3-related disorders (achondroplasia, thanatophoric dysplasia, hypochondroplasia) are primarily caused by gain-of-function missense variants, not loss-of-function truncating variants.	pvs1_gene_context
BP2	Not assessed	BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No phase information or co-occurring variant data are available.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene or gene product. BayesDel (0.157) is below typical pathogenic thresholds and predicts a benign effect. SpliceAI (max delta 0.0) predicts no splicing alteration. Together, these constitute multiple lines of evidence supporting a neutral effect, meeting BP4 at supporting strength.	bayesdel spliceai
BP5	Not met	BP5 requires the variant to be observed in a case with an alternate molecular basis for disease. No such case data are available.
BP6	Not assessed	BP6 requires classification as benign by a reputable source. The variant is absent from ClinVar, and no clinical laboratory or expert panel has classified it as benign.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant is a missense substitution (c.1267G>A, p.Val423Met) and therefore does not meet the variant type requirement for BP7.

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