Variant classification summary

NM_000142.4:c.1959C>T

FGFR3 · NP_000133.1:p.(Asn653=) · NM_000142.4

GRCh37: chr4:1807900 C>T · GRCh38: chr4:1806173 C>T

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.(Asn653=)

gnomAD AF

1.736291974858492e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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

3

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).

Final determination: 1 supporting pathogenic (PM2) + 1 supporting benign (BP4) does not meet any combination threshold, so VUS.

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	Not applicable: as a synonymous change (p.Asn653=), no null-variant mechanism such as nonsense-mediated decay or truncation is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: as a synonymous change (p.Asn653=), no altered amino acid exists to compare against a previously pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing results, pedigree, or confirmed de novo documentation were available.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional or splicing assay data for this variant was available.
PS4	Not assessed	Not assessed: no case-control enrichment or affected-case series data for this exact variant was available.
PM1	N/A	Not applicable: no missense change exists to evaluate for mutational-hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	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 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no second allele, phase information, or biallelic inheritance evidence was available.
PM4	N/A	Not applicable: the protein sequence is unchanged, so no protein-length alteration exists to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: as a synonymous change, no missense change exists at this residue to compare with a pathogenic one.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no documentation of a presumed de novo occurrence with compatible phenotype was available.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree, affected relatives, or informative meioses were available to test co-segregation.	generic_acmg_combination_rules
PP2	N/A	Not applicable: missense-constraint properties are irrelevant because no missense change is present.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.00 is well below the >0.2 PP3 threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no clinical phenotype was provided, so phenotype-to-disease specificity could not be evaluated.
PP5	Not met	Not met: the only ClinVar submission is a laboratory Uncertain-significance call with no expert-panel pathogenic assertion.	clinvar
BA1	Not met	Not met: highest gnomAD v4.1 ancestry-specific AF 0.09862% is far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: maximum population AF 0.09862% is below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no disease-focused cohort or validated unaffected-adult observations were available.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay data demonstrating a benign, wild-type-like effect was available.
BS4	Not assessed	Not assessed: no family data demonstrating lack of segregation was available.	generic_acmg_combination_rules
BP1	N/A	Not applicable: no missense change is present, so the gene's truncating-disease mechanism is irrelevant here.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second variant or cis/trans phase data was available to establish a benign allelic relationship.
BP3	N/A	Not applicable: protein length is unchanged, so the repetitive-region in-frame indel criterion has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI max delta 0.00 is below the <0.1 BP4 threshold, indicating no predicted splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternative molecular explanation or patient phenotype was documented to evaluate.
BP6	Not met	Not met: no expert-panel benign assertion exists; the only ClinVar submission is a laboratory Uncertain-significance call.	clinvar
BP7	Not assessed	Not assessed: no conservation metric (e.g., GERP/phyloP) was available, and the splice signal is already credited to BP4.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.