NM_002253.3:c.3247A>T

KDR · NP_002244.1:p.(Thr1083Ser) · NM_002253.3

GRCh37: chr4:55955915 T>A · GRCh38: chr4:55089748 T>A

Gene: KDR Transcript: NM_002253.3

Final call

VUS

PM2 supporting

Variant details

Gene

KDR

Transcript

NM_002253.3

Protein

NP_002244.1:p.(Thr1083Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002253.3:c.3247A>T (p.Thr1083Ser) in KDR is a missense variant in exon 24. It is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level.

No variant-specific functional studies, case-control data, family segregation data, or de novo observations are available. The variant is absent from ClinVar and has not been reported in any peer-reviewed publication.

Computational predictors are conflicting: REVEL 0.638 suggests a deleterious effect, while BayesDel -0.0950088 predicts benign, and SpliceAI shows no splicing impact (max delta = 0.00). PP3 and BP4 are not met.

The only applicable criterion is PM2 (supporting). Under generic ACMG/AMP 2015 combination rules (PMID:25741868), a single supporting criterion is insufficient to classify the variant as likely pathogenic or likely benign. The variant defaults to a classification of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_002253.3:c.3247A>T (p.Thr1083Ser) is a missense substitution. The ClinGen SVI PVS1 framework (PMC6185798) applies only to null variants (nonsense, frameshift, canonical ±1,2 splice). This missense variant does not qualify for PVS1.	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at c.3247 resulting in p.Thr1083Ser has been established as pathogenic. No ClinVar entries exist for any variant at this codon.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for NM_002253.3:c.3247A>T in any available source.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for p.Thr1083Ser. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence curated.	oncokb
PS4	Not met	No case-control data or cohort enrichment data are available for this variant. The variant has not been reported in any affected individual cohort.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion (Richards et al., PMID:25741868). No applicable framework for this criterion exists under generic ACMG.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot (Cancer Hotspots negative). No evidence that residue 1083 resides within a critical functional domain with established pathogenic enrichment.
PM2	Met	NM_002253.3:c.3247A>T is completely absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). This meets the non-VCEP PM2 threshold of allele frequency <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic missense comparator variant (different amino acid change at codon 1083) was identified in ClinVar. PM5 candidate harvesting yielded zero candidates.	pm5_candidates
PM6	Not met	No de novo observation (with or without confirmed parentage) has been reported for this variant in any available source.
PP1	Not met	No cosegregation data available for this variant; no family studies identified in any evidence source.
PP2	Not met	No gene-level constraint data (missense Z-score, HCI prior) are available for KDR to determine whether the gene has a low rate of benign missense variation. PP2 cannot be applied without this evidence.
PP3	Not met	Computational evidence is conflicting. REVEL score 0.638 supports a deleterious prediction, but BayesDel score -0.0950088 predicts a benign effect. SpliceAI shows no splicing impact (max delta = 0.00). No consensus across multiple in silico tools.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available to evaluate whether the proband's features are highly specific for a KDR-related disorder.
PP5	N/A	PP5 is not a standard ACMG/AMP 2015 criterion (Richards et al., PMID:25741868). No applicable framework for this criterion exists under generic ACMG.
BA1	Not met	Variant is absent from all population databases. Allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from all population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3% for non-VCEP assessment.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in a homozygous state in healthy adults or at high allele frequency in a recessive disease context. The variant is absent from all population databases.
BS3	Not met	No well-established functional studies demonstrating a benign or neutral effect have been identified for p.Thr1083Ser.
BS4	Not met	No segregation or nonsegregation data available. No family studies involving this variant have been reported.
BP1	Not met	While KDR loss of function is supported as a germline disease mechanism by targeted literature review, there is insufficient evidence to conclude that only truncating variants cause disease and that missense variants are not pathogenic. In the absence of gene-specific BP1 calibration data, this criterion cannot be applied.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in KDR. No phase data available.
BP4	Not met	Computational evidence is conflicting and does not provide multiple lines of support for a benign interpretation. REVEL 0.638 is deleterious-leaning while BayesDel -0.0950088 is benign-leaning. SpliceAI shows no splicing impact (max delta = 0.00). Evidence does not meet the 'multiple lines' threshold for BP4.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in an individual with an alternate molecular cause for disease. No case data available.
BP6	Not met	This variant has not been reported as benign by a reputable source. It is absent from ClinVar entirely.	clinvar
BP7	N/A	NM_002253.3:c.3247A>T (p.Thr1083Ser) is a missense variant, not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.

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.