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.1 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.2 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.3 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.4 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.5
FGFR3
Final classification
VUS
PM2BP4
FGFR3
c.1267G>A
p.Val423Met
This variant
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.
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FGFR3 c.1267G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_000142.4 · variants mapped to exon structure
FGFR3
NM_000142.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: absent.gnomAD v4.1: AF=6.45e-07 (1/1549
✓
BP4
supporting
Benign
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: 0.157 (benign-leaningbelow typical pathogenic thresholds).SpliceAI: max delta 0.0 (no predicted splice impact).
Assessed · not applied
· 10 not met · 10 not assessed
Pathogenic
PS1
No different nucleotide change at the same codon (c.1267) has been identified as pathogenic.
PS2
De novo confirmation requires parental genotype data demonstrating the variant arose de novo.
PS3
No well-established in vitro or in vivo functional studies have been identified for NM_000142.4:c.1267G>A (p.Val423Met).
PS4
No case-control data demonstrate increased prevalence in affected individuals versus controls.
PM1
This variant is not located in a statistically significant mutational hotspot.
PM6
No de novo occurrence has been reported for this variant.
PP1
No cosegregation data are available for this variant.
PP2
PP2 requires gene-level missense constraint metrics (e.g., missense Z-score) demonstrating a low rate of benign missense variation.
PP3
In silico predictions are discordant.
PP4
No patient phenotype or clinical information is available for PP4 assessment.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in population databases.
BS1
BS1 requires an allele frequency >0.3% in population databases.
BS2
BS2 requires observation in a homozygous state in healthy adults or at a frequency inconsistent with disease penetrance.
BS3
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
BS4 requires lack of segregation in affected family members.
BP1
BP1 requires a missense variant in a gene where primarily truncating variants cause disease.
BP2
BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant.
BP5
BP5 requires the variant to be observed in a case with an alternate molecular basis for disease.
BP6
BP6 requires classification as benign by a reputable source.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.4529e-07; MAF= 0.00006%, 1/1549690 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.19005e-05; MAF= 0.00119%, 1/84030 alleles, homozygotes = 0).
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
6.5e-05%
· 1 / 1,549,690
0 hom
0 hom
South Asian 1 / 84,030 |
0.0012% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.566. BayesDel score = 0.157233.
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. FGFR3, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancers, most frequently in bladder c
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.
Sources & reference links