About PDGFRA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PDGFRA c.1988C>T, p.(Ala663Val)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,607,834 alleles), meeting the allele frequency threshold for PM2 supporting (<0.1% in population databases).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product. BayesDel predicts a benign score (0.21064, below the 0.3 threshold). SpliceAI predicts no splicing impact (max delta score = 0.00). Two independent in silico tools converge on a neutral/benign prediction.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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
0 / 1,607,834 alleles
gnomAD v4.1: 0 / 1,607,834 alleles. Recorded AF 0. Recorded homozygote count 0.
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.
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. PDGFRA, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in a diverse range of 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.
29 criteria with recorded statuses: 2 met · 22 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_006206.5:c.1988C>T (p.Ala663Val) is a missense variant in exon 14 of PDGFRA, a receptor tyrosine kinase gene.
This variant is absent from gnomAD v2.1 and v4.1 (0/1,607,834 alleles), meeting PM2 at supporting strength.
In silico analysis yields conflicting predictions: REVEL score of 0.755 suggests a damaging effect, but BayesDel (0.21064) and SpliceAI (max delta 0.00) predict a benign/no-impact outcome. Multiple lines of computational evidence do not converge on pathogenicity; PP3 is not met.
BayesDel and SpliceAI independently predict no deleterious effect, meeting BP4 at supporting benign strength.
This variant is absent from ClinVar; no pathogenic or benign classification exists from any expert panel or clinical laboratory. PS1, PS5, PM5, PP5, and BP6 cannot be applied.
No functional studies, de novo reports, case-control data, segregation data, or publications mentioning this specific variant were identified. PS2, PS3, PS4, PM6, PP1, PP4, BS2, BS3, BS4, BP2, and BP5 are not met.
The variant is not located in a statistically significant mutational hotspot and no domain-level enrichment data support PM1.
The gene-level PVS1 review does not provide robust evidence that PDGFRA disease is primarily caused by truncating variants; BP1 is not met. PVS1 is not applicable to this missense variant.
PM2 (supporting pathogenic) and BP4 (supporting benign) are both met; the evidence is balanced and does not reach a classification threshold in either direction.
Using the generic ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,607,834 alleles), meeting the allele frequency threshold for PM2 supporting (<0.1% in population databases). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: 0/1
- 607
- 834 alleles (AF=0.00%). Absent across all subpopulations.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. BayesDel predicts a benign score (0.21064, below the 0.3 threshold). SpliceAI predicts no splicing impact (max delta score = 0.00). Two independent in silico tools converge on a neutral/benign prediction. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.21064 (benign
- below 0.3 threshold). SpliceAI: max delta 0.00 (no predicted splice impact). Two independent lines of computational evidence suggest no deleterious effect.
Sources
bayesdelspliceai ↗
Not met · 22 · evaluated, threshold not reached
PS1 No other nucleotide change at this position (p.Ala663) has been reported as pathogenic. This variant is absent from ClinVar; no comparator nucleotide change producing the same amino acid change exists to support PS1. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no established pathogenic variant at this residue with a different nucleotide change.
Sources
PS2 No de novo evidence (with confirmed paternity/maternity) is available for this variant. No publications or case reports document this variant occurring as a de novo event. Details ▾Hide ▴
Evidence considered
- No de novo data available
- no family-based studies identified.
Still missing
- No trio or parent-of-origin testing data available for this variant.
PS3 No well-established in vitro or in vivo functional studies supporting a damaging effect have been identified for this variant. OncoKB classifies this variant as Unknown Oncogenic Effect and reports no variant-specific functional evidence. No publications with functional data for p.Ala663Val were found. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data. No literature functional studies identified.
Still missing
- No experimental functional characterization of p.Ala663Val has been published.
Sources
PS4 No case-control or cohort data demonstrate significantly increased prevalence of this variant in affected individuals compared to controls. The variant is absent from ClinVar and COSMIC; no patient-based statistical evidence is available. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar (no patient submissions). Absent from COSMIC (no somatic tumor reports). No case-control studies available.
Still missing
- No case-control or cohort enrichment data available.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org). While residue A663 is located in the PDGFRA tyrosine kinase domain, no domain-level evidence establishes that missense variants in this specific region are enriched among pathogenic variants. COSMIC reports no entries at this residue. Details ▾Hide ▴
Evidence considered
- Not a statistically significant hotspot at cancerhotspots.org. No COSMIC entries at this position. No domain-level enrichment data for PDGFRA kinase domain missense variants.
Still missing
- No residue-specific or domain-level enrichment analysis available.
PM5 No different missense change at codon 663 has been reported as pathogenic. PM5 candidate analysis found zero same-residue candidates in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue candidates. No pathogenic ClinVar entries at codon 663 with a different amino acid change.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence data (without confirmation of paternity/maternity) are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No de novo studies or case reports available.
PP1 No co-segregation data are available for this variant. No family-based linkage or segregation studies have been reported. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No pedigree or co-segregation analysis available.
PP2 No gene-level constraint metrics (z-score, missense constraint) are available for PDGFRA in the evidence set. HCI prior probability was not calculable for this gene. PP2 cannot be applied without demonstrated low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported. No gnomAD missense constraint (z-score) or gene-level constraint data available.
Still missing
- Gene-level missense constraint data (e.g.
- gnomAD missense z-score
- LOEUF) not available in evidence brief.
PP3 In silico evidence is conflicting. REVEL score is 0.755 (damaging), but BayesDel score is 0.21064 (benign) and SpliceAI predicts no splicing impact (max delta 0.00). Multiple lines of computational evidence do not converge on a deleterious effect; only one tool (REVEL) supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.755 (damaging). BayesDel: 0.21064 (benign). SpliceAI: max delta 0.00 (no splice impact). Conflicting in silico predictions
- no convergence on deleterious effect.
Sources
PP4 No patient phenotype or family history information is available to assess phenotype specificity. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype or clinical data provided.
Still missing
- No patient phenotype or family history data available.
PP5 This variant is absent from ClinVar. No reputable source, expert panel, or clinical laboratory has classified this variant as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No expert panel or clinical diagnostic laboratory classification available.
Sources
BA1 This variant is absent from gnomAD (0/1,607,834 alleles in v4.1). Allele frequency is 0.00%, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0/1
- 607
- 834 alleles (AF=0.00%). Far below BA1 threshold of >1%.
Sources
BS1 This variant is absent from gnomAD (0/1,607,834 alleles in v4.1). Allele frequency is 0.00%, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0/1
- 607
- 834 alleles (AF=0.00%). Far below BS1 threshold of >0.3%.
Sources
BS2 No data on observation in healthy adults are available. BS2 requires the variant to be observed in a healthy adult individual for a recessive, or in trans with a pathogenic variant for a dominant, disorder with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data available.
Still missing
- No data on variant occurrence in healthy adult controls with expected full penetrance.
BS3 No well-established in vitro or in vivo functional studies show no deleterious effect for this variant. No functional studies of any kind were identified for p.Ala663Val. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant.
Still missing
- No functional characterization data available.
BS4 No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No pedigree or co-segregation analysis available.
BP1 The gene-level PVS1 context review identified papers mentioning PDGFRA, but these papers do not establish that PDGFRA disease is primarily caused by truncating variants. The supporting publications discuss SDH-deficient GISTs that are KIT/PDGFRA mutation-negative, or describe SDHA germline variants with incidental somatic PDGFRA driver mutations — they do not demonstrate PDGFRA loss-of-function as a primary germline disease mechanism. BP1 requires robust evidence that the gene causes disease primarily through truncating variants; this evidence is absent. Details ▾Hide ▴
Evidence considered
- PVS1 gene context review cites papers mentioning PDGFRA only in the context of SDH-deficient GISTs (where PDGFRA is mutation-negative) or incidental somatic mutations. No evidence that PDGFRA disease is primarily caused by truncating variants.
Still missing
- No robust evidence that PDGFRA is primarily a LoF/haploinsufficiency disease gene.
Sources
pvs1_gene_context
BP2 No data on observation in trans with a pathogenic variant are available. Details ▾Hide ▴
Evidence considered
- No trans-phase variant data available.
Still missing
- No data on observation in trans.
BP5 No evidence of an alternate molecular basis for disease in a case harboring this variant is available. Details ▾Hide ▴
Evidence considered
- No data on alternate molecular diagnoses in individuals with this variant.
Still missing
- No clinical data on alternative genetic findings in individuals with this variant.
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
PS5 No reputable source (e.g., ClinVar expert panel) has classified this variant as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source classification available.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Ala663Val); does not fall into PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 framework is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Variant class is missense substitution
- PVS1 applies only to null variants per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ASkipped per case instructions; not assessed. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per case instructions; variant is a substitution, not a protein-length-altering change. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AIn-frame deletion/insertion criterion; variant is a single-nucleotide substitution (missense), not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame deletion/insertion.
BP7 N/AThis is a missense variant (p.Ala663Val), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Identifiers
- Gene
- PDGFRA
- Transcript
- NM_006206.5
- Coding (HGVS c.)
- NM_006206.5:c.1988C>T
- Protein (HGVS p.)
- NP_006197.1:p.(Ala663Val)
- GRCh38
- chr4:54277992 C>T
- GRCh37
- chr4:55144159 C>T
Gene diagram
Every interpreted variant in PDGFRA, mapped onto the exon structure of NM_006206.5. Select a row to find it on the plot.
PDGFRANM_006206.5
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 PDGFRA
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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
0 / 1,607,834 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,607,834 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1607834 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74866 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.755
- BayesDel
- 0.211
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. BayesDel predicts a benign score (0.21064, below the 0.3 threshold). SpliceAI predicts no splicing impact (max delta score = 0.00). Two independent in silico tools converge on a neutral/benign prediction. Details ▾Hide ▴
Evidence considered
- BayesDel: 0.21064 (benign
- below 0.3 threshold). SpliceAI: max delta 0.00 (no predicted splice impact). Two independent lines of computational evidence suggest no deleterious effect.
Sources
bayesdelspliceai ↗
PP3 In silico evidence is conflicting. REVEL score is 0.755 (damaging), but BayesDel score is 0.21064 (benign) and SpliceAI predicts no splicing impact (max delta 0.00). Multiple lines of computational evidence do not converge on a deleterious effect; only one tool (REVEL) supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.755 (damaging). BayesDel: 0.21064 (benign). SpliceAI: max delta 0.00 (no splice impact). Conflicting in silico predictions
- no convergence on deleterious effect.
Sources
BP7 N/AThis is a missense variant (p.Ala663Val), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.755. BayesDel score = 0.21064.
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
0 / 1,607,834 recorded alleles
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_006206.5%3Ac.1988C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55144159-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-54277992-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-54277992-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006206.5%3Ac.1988…
- OncoKB ↗www.oncokb.org/gene/PDGFRA/A663V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PDGFRA+c.1988C%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
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1607834 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74866 alleles, homozygotes = 0).
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 = 0.755. BayesDel score = 0.21064.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PDGFRA, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in a diverse range of 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.