About KDR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KDR c.3247A>T, p.(Thr1083Ser)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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%.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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; combination = 1 supporting, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
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. KDR, a receptor tyrosine kinase, is altered by mutation or amplification in various cancers, most frequently in skin cancers.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 20 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 1
PM2 SupportingNM_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%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AC=0).
- Absent from gnomAD v4.1 (AC=0).
- Absent from gnomAD-Canada v1.0 (AC=0).
Still missing
- No structural variant or deep intronic coverage assessment.
Sources
Not met · 20 · evaluated, threshold not reached
PS1 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. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for this variant or any alternative nucleotide change at codon 1083.
Still missing
- No pathogenic comparator variant at same amino acid residue.
Sources
PS2 No de novo observation with confirmed paternity and maternity has been reported for NM_002253.3:c.3247A>T in any available source. Details ▾Hide ▴
Evidence considered
- No de novo data identified in ClinVar
- literature_pass
- or any reviewed publication.
Still missing
- No pedigree or de novo testing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No variant-specific functional evidence in literature_pass (0 PMIDs found).
Still missing
- No functional studies available for this variant.
Sources
PS4 No case-control data or cohort enrichment data are available for this variant. The variant has not been reported in any affected individual cohort. Details ▾Hide ▴
Evidence considered
- No affected-vs-control prevalence data identified in any evidence source.
Still missing
- No case-control or cohort enrichment data.
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: variant not located in a significant hotspot.
Still missing
- No domain-level constraint or pathogenic enrichment data available for this residue.
PM6 No de novo observation (with or without confirmed parentage) has been reported for this variant in any available source. Details ▾Hide ▴
Evidence considered
- No de novo report identified in ClinVar
- literature_pass
- or any reviewed publication.
Still missing
- No de novo testing or trio data available.
PP1 No cosegregation data available for this variant; no family studies identified in any evidence source. Details ▾Hide ▴
Evidence considered
- No family or cosegregation data identified.
Still missing
- No family studies or cosegregation analysis.
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. PP2 cannot be applied without this evidence. Details ▾Hide ▴
Evidence considered
- HCI prior not available for KDR.
- No gnomAD missense constraint data in evidence_brief.
Still missing
- No missense constraint metrics available for KDR.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.638 (deleterious-leaning).
- BayesDel: -0.0950088 (benign-leaning).
- SpliceAI: max delta 0.00 (no splicing impact).
Still missing
- No HCI prior score available.
Sources
PP4 No patient phenotype or clinical data are available to evaluate whether the proband's features are highly specific for a KDR-related disorder. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data provided.
Still missing
- No patient phenotype or clinical history available.
BA1 Variant is absent from all population databases. Allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
- AF = 0.
Sources
BS1 Variant is absent from all population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3% for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
- AF = 0.
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- No homozygous count data available
- variant absent from population databases.
Still missing
- No homozygous or hemizygous observation data.
BS3 No well-established functional studies demonstrating a benign or neutral effect have been identified for p.Thr1083Ser. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating a benign effect identified.
Still missing
- No functional data available for this variant.
BS4 No segregation or nonsegregation data available. No family studies involving this variant have been reported. Details ▾Hide ▴
Evidence considered
- No family segregation data identified.
Still missing
- No family studies or segregation analysis 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. In the absence of gene-specific BP1 calibration data, this criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- KDR LoF mechanism supported
- but no evidence that missense variants are exclusively benign.
Still missing
- No gene-specific BP1 calibration data
- uncertain whether missense variants are benign in KDR.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic variant in KDR. No phase data available. Details ▾Hide ▴
Evidence considered
- No phased variant data or observation in trans with a pathogenic variant.
Still missing
- No phase or in-trans observation data.
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.638 (deleterious-leaning)
- BayesDel -0.0950088 (benign-leaning)
- SpliceAI 0.00 (no impact). Conflicting predictions.
Still missing
- Conflicting in silico predictions
- no consensus.
Sources
BP5 No observation of this variant in an individual with an alternate molecular cause for disease. No case data available. Details ▾Hide ▴
Evidence considered
- No observation in a case with an alternate molecular diagnosis.
Still missing
- No case data available.
BP6 This variant has not been reported as benign by a reputable source. It is absent from ClinVar entirely. Details ▾Hide ▴
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null-variant type eligible for PVS1 per PMC6185798.
Sources
PM5 N/ANo same-residue pathogenic missense comparator variant (different amino acid change at codon 1083) was identified in ClinVar. PM5 candidate harvesting yielded zero candidates. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants identified
- PM5 not applicable.
Sources
pm5_candidates
PP5 N/APP5 is not a standard ACMG/AMP 2015 criterion (Richards et al., PMID:25741868). No applicable framework for this criterion exists under generic ACMG. Details ▾Hide ▴
Evidence considered
- Not a standard ACMG/AMP criterion.
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion (Richards et al., PMID:25741868). No applicable framework for this criterion exists under generic ACMG. Details ▾Hide ▴
Evidence considered
- Not a standard ACMG/AMP criterion.
Identifiers
- Gene
- KDR
- Transcript
- NM_002253.3
- Coding (HGVS c.)
- NM_002253.3:c.3247A>T
- Protein (HGVS p.)
- NP_002244.1:p.(Thr1083Ser)
- GRCh38
- chr4:55089748 T>A
- GRCh37
- chr4:55955915 T>A
Gene diagram
Every interpreted variant in KDR, mapped onto the exon structure of NM_002253.3. Select a row to find it on the plot.
KDRNM_002253.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KDR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.638
- BayesDel
- -0.095
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.638 (deleterious-leaning).
- BayesDel: -0.0950088 (benign-leaning).
- SpliceAI: max delta 0.00 (no splicing impact).
Still missing
- No HCI prior score available.
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL 0.638 (deleterious-leaning)
- BayesDel -0.0950088 (benign-leaning)
- SpliceAI 0.00 (no impact). Conflicting predictions.
Still missing
- Conflicting in silico predictions
- no consensus.
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.638. BayesDel score = -0.0950088.
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
Captured gnomAD v4.1 source record
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002253.3%3Ac.3247A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55955915-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-55089748-T-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-55089748-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002253.3%3Ac.3247…
- OncoKB ↗www.oncokb.org/gene/KDR/T1083S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KDR+c.3247A%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
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 = 0.638. BayesDel score = -0.0950088.
Functional
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.
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.