Classification rationale

PM2 BP4 VUS

FGFR3 c.1959C>T synonymous · exon 14

PM2 (Supporting): variant is rare in gnomAD v4.1, with overall AF 0.00174% and highest ancestry-specific AF 0.09862%, both below the 0.1% threshold, and zero homozygotes. BP4 (Supporting): SpliceAI max delta 0.00 is below the <0.1 threshold, indicating no predicted splice impact. With only these two supporting findings and no pathogenic or benign evidence beyond them, the generic ACMG/AMP 2015 combination rules classify this variant as a Variant of Uncertain Significance (VUS).

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 · 18 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 review Pathogenic

Met (supporting): overall AF 0.00174% and highest ancestry-specific AF 0.09862% in gnomAD v4.1, both below the 0.1% threshold, with zero homozygotes. Flagged for human review: the ancestry-specific call rests on only 6 alleles and sits close to the cutoff.

gnomAD v4.1 reports 28/1,612,632 alleles, overall AF 1.73629e-05 (0.00174%), zero homozygotes, and maximum group AF 0.00042888.The highest v4.1 ancestry-specific value is 6/6084 Middle Eastern alleles, AF 0.000986193 (0.09862%), just below the generic PM2 cutoff of 0.1%; no homozygotes were observed in that population.gnomAD v2.1 reports 7/248,438 alleles, overall AF 2.8176e-05 (0.00282%), zero homozygotes, and grpmax FAF 7.13e-06.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.00 is below the <0.1 BP4 threshold, indicating no predicted splice impact.

SpliceAI Lookup for NM_000142.4:c.1959C>T (hg37) returned max delta score = 0.00 (pangolin_SG=0.052, pangolin_SL=-0.006), below the generic fallback's BP4 threshold of <0.1 for synonymous/intronic/non-canonical-splice variants, supporting no predicted splice impact.No BayesDel evidence was used: per pipeline calibration policy, BayesDel has no verified published threshold available and is never usable for PP3/BP4 regardless of any recalled cutoff.

spliceai ↗

Assessed · not applied · 5 not met · 13 not assessed

Pathogenic

PS2 Not assessed: no parental testing results, pedigree, or confirmed de novo documentation were available.

PS3 Not assessed: no functional or splicing assay data for this variant was available.

PS4 Not assessed: no case-control enrichment or affected-case series data for this exact variant was available.

PM3 Not assessed: no second allele, phase information, or biallelic inheritance evidence was available.

PM6 Not assessed: no documentation of a presumed de novo occurrence with compatible phenotype was available.

PP1 Not assessed: no pedigree, affected relatives, or informative meioses were available to test co-segregation.

PP3 Not met: SpliceAI max delta 0.00 is well below the >0.2 PP3 threshold.

PP4 Not assessed: no clinical phenotype was provided, so phenotype-to-disease specificity could not be evaluated.

PP5 Not met: the only ClinVar submission is a laboratory Uncertain-significance call with no expert-panel pathogenic assertion.

Benign

BA1 Not met: highest gnomAD v4.1 ancestry-specific AF 0.09862% is far below the 1% BA1 threshold.

BS1 Not met: maximum population AF 0.09862% is below the 0.3% BS1 threshold.

BS2 Not assessed: no disease-focused cohort or validated unaffected-adult observations were available.

BS3 Not assessed: no functional assay data demonstrating a benign, wild-type-like effect was available.

BS4 Not assessed: no family data demonstrating lack of segregation was available.

BP2 Not assessed: no second variant or cis/trans phase data was available to establish a benign allelic relationship.

BP5 Not assessed: no alternative molecular explanation or patient phenotype was documented to evaluate.

BP6 Not met: no expert-panel benign assertion exists; the only ClinVar submission is a laboratory Uncertain-significance call.

BP7 Not assessed: no conservation metric (e.g., GERP/phyloP) was available, and the splice signal is already credited to BP4.

N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.73629e-05; MAF= 0.00174%, 28/1612632 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000986193; MAF= 0.09862%, 6/6084 alleles, homozygotes = 0); grpmax FAF= 0.00042888.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.8176e-05; MAF= 0.00282%, 7/248438 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000329598; MAF= 0.03296%, 2/6068 alleles, homozygotes = 0); grpmax FAF= 7.13e-06.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0017% · 28 / 1,612,632
0 hom · FAF 0.043%

Middle Eastern 6 / 6,084	0.099%
Remaining individuals 2 / 62,432	0.0032%
East Asian 1 / 44,868	0.0022%
South Asian 2 / 91,058	0.0022%
European (non-Finnish) 16 / 1,179,660	0.0014%
African/African American 1 / 74,926	0.0013%

+ 4 not observed (Admixed American, European (Finnish), Amish, Ashkenazi Jewish)

gnomAD v2.1

0.0028% · 7 / 248,438
0 hom · FAF 0.00071%

Remaining individuals 2 / 6,068	0.033%
East Asian 1 / 18,320	0.0055%
South Asian 1 / 30,556	0.0033%
European (non-Finnish) 3 / 111,778	0.0027%

+ 4 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish))

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2068953)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots