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
FGFR3 c.1267G>A · p.Val423Met
FGFR3
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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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