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.1 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.2 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.3 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.4
KDR
Final classification
VUS
KDR c.3247A>T · p.Thr1083Ser
KDR
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.
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; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
KDR c.3247A>T
PM2
→
VUS
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_002253.3 · variants mapped to exon structure
KDR
NM_002253.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 20 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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%.
Absent from gnomAD v2.1 (AC=0).Absent from gnomAD v4.1 (AC=0).Absent from gnomAD-Canada v1.0 (AC=0).
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at c.3247 resulting in p.Thr1083Ser has been established as pathogenic.
PS2
No de novo observation with confirmed paternity and maternity has been reported for NM_002253.3:c.3247A>T in any available source.
PS3
No well-established in vitro or in vivo functional studies have been identified for p.Thr1083Ser.
PS4
No case-control data or cohort enrichment data are available for this variant.
PM1
The variant does not lie in a statistically significant mutational hotspot (Cancer Hotspots negative).
PM6
No de novo observation (with or without confirmed parentage) has been reported for this variant in any available source.
PP1
No cosegregation data available for this variant; no family studies identified in any evidence source.
PP2
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.
PP3
Computational evidence is conflicting.
PP4
No patient phenotype or clinical data are available to evaluate whether the proband's features are highly specific for a KDR-related disorder.
Benign
BA1
Variant is absent from all population databases.
BS1
Variant is absent from all population databases.
BS2
No observation of this variant in a homozygous state in healthy adults or at high allele frequency in a recessive disease context.
BS3
No well-established functional studies demonstrating a benign or neutral effect have been identified for p.Thr1083Ser.
BS4
No segregation or nonsegregation data available.
BP1
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.
BP2
No observation of this variant in trans with a known pathogenic variant in KDR.
BP4
Computational evidence is conflicting and does not provide multiple lines of support for a benign interpretation.
BP5
No observation of this variant in an individual with an alternate molecular cause for disease.
BP6
This variant has not been reported as benign by a reputable source.
N/A · 4
PVS1 · PM5 · PP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.638. BayesDel score = -0.0950088.
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. KDR, a receptor tyrosine kinase, is altered by mutation or amplification in various cancers, most frequently in skin cancers.
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