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FGFR3c.1267G>AUncertain significance
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Variant interpretation report

FGFR3 c.1267G>A, p.(Val423Met)

NM_000142.4:c.1267G>A NP_000133.1:p.(Val423Met) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About FGFR3

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 10 not met · 11 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

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.

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.

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: AF=6.45e-07 (1/1
  • 549
  • 690 alleles
  • 0 homozygotes)
  • highest in South Asian (AF=1.19e-05).
  • gnomAD-Canada v1.0: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.157 (benign-leaning
  • below typical pathogenic thresholds).
  • SpliceAI: max delta 0.0 (no predicted splice impact).
Sources
bayesdelspliceai ↗

Not met · 10 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant at c.1267 identified in ClinVar or literature.
Still missing
  • No comparator nucleotide change data at codon 423.
Sources
clinvar ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • gnomAD v4.1 prevalence (1/1
  • 549
  • 690) insufficient for case-control comparison.
Still missing
  • No case-control or cohort enrichment data.
Sources
gnomad_v4 ↗clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots analysis: not in a statistically significant hotspot
  • no FGFR3-specific PM1 domain rule available.
Still missing
  • No FGFR3-specific domain-level PM1 rule from CSPEC/VCEP.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.566 (pathogenic-leaning).
  • BayesDel: 0.157 (benign-leaning).
  • SpliceAI: max delta 0.0 (no splice impact).
Sources
revelbayesdelspliceai ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: max subpopulation AF = 1.19e-05 (South Asian)
  • far below BA1 threshold of 1%.
Sources
gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: max subpopulation AF = 1.19e-05 (South Asian)
  • far below BS1 threshold of 0.3%.
Sources
gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • Zero homozygotes in all gnomAD datasets
  • only 1 heterozygous observation in gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS4 BS4 requires lack of segregation in affected family members. No family segregation studies are available to evaluate this criterion. Details ▾Hide ▴
Still missing
  • No family segregation data.
BP1 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. Details ▾Hide ▴
Evidence considered
  • FGFR3 disease mechanism: gain-of-function missense variants
  • not truncating variants. BP1 not applicable to this gene.
Sources
pvs1_gene_context
BP5 BP5 requires the variant to be observed in a case with an alternate molecular basis for disease. No such case data are available. Details ▾Hide ▴
Still missing
  • No case data with alternate molecular diagnoses.

Not assessed · 11 · no assessment recorded

PS2 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. Details ▾Hide ▴
Still missing
  • Parental genotype data or trio sequencing not available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional data curated.
Still missing
  • No functional characterization of the V423M variant in the FGFR3 tyrosine kinase domain.
Sources
oncokb ↗
PM6 No de novo occurrence has been reported for this variant. PM6 requires confirmation that the variant arose de novo with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
  • No de novo testing or family studies available.
PP1 No cosegregation data are available for this variant. PP1 requires demonstration of segregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
  • No family studies or cosegregation analysis.
PP2 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. Details ▾Hide ▴
Still missing
  • No missense constraint metrics (Z-score
  • MTR) available for FGFR3.
PP4 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. Details ▾Hide ▴
Still missing
  • No patient phenotype or clinical context provided.
PP5 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no reputable source classification available.
Still missing
  • No clinical laboratory or expert panel classification.
Sources
clinvar ↗
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. Details ▾Hide ▴
Still missing
  • No functional studies evaluating the effect of V423M on FGFR3 activity.
BP2 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. Details ▾Hide ▴
Still missing
  • No phase data or co-occurring variant analysis.
BP6 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no reputable source has classified this variant as benign.
Still missing
  • No clinical laboratory classification.
Sources
clinvar ↗
PS5 No established pathogenic classification from a reputable source with supporting functional (PS3) and prevalence (PS4) evidence is available for this variant. Details ▾Hide ▴
Still missing
  • No independent occurrences with validated functional evidence.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a null variant class eligible for PVS1.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: no same-residue pathogenic comparators found.
Sources
pm5_candidates
BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
FGFR3
Transcript
NM_000142.4
Coding (HGVS c.)
NM_000142.4:c.1267G>A
Protein (HGVS p.)
NP_000133.1:p.(Val423Met)
GRCh38
chr4:1804824 G>A
GRCh37
chr4:1806551 G>A

Gene diagram

Every interpreted variant in FGFR3, mapped onto the exon structure of NM_000142.4. Select a row to find it on the plot.

FGFR3NM_000142.4
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,549,690 alleles AF 6.45e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.5e-07 · 1 / 1,549,690 alleles · 0 hom
South Asian1 / 84,030 1.2e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.260
Pangolin splice gain
0.090

Other predictors

REVEL
0.566
BayesDel
0.157

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.157 (benign-leaning
  • below typical pathogenic thresholds).
  • SpliceAI: max delta 0.0 (no predicted splice impact).
Sources
bayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.566 (pathogenic-leaning).
  • BayesDel: 0.157 (benign-leaning).
  • SpliceAI: max delta 0.0 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.566. BayesDel score = 0.157233.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,549,690 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.