About PDCD10
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PDCD10 c.345T>G, p.(Ser115Arg)
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_007217.3:c.345T>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0), well below the 0.1% threshold for a rare variant in a gene associated with autosomal dominant familial cerebral cavernous malformations. Absence from large population databases supports pathogenicity at a supporting level.
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
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
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: 1 met · 24 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_007217.3:c.345T>G (p.Ser115Arg) in PDCD10 is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at a supporting level.
The only criterion met is PM2 (supporting); no other pathogenic or benign criteria are satisfied. According to the generic ACMG/AMP 2015 combination rules (PMID:25741868), a single supporting criterion is insufficient for classification as likely pathogenic or likely benign. The variant remains a variant of uncertain significance (VUS).
No criteria match.
Met · 1
PM2 SupportingNM_007217.3:c.345T>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0), well below the 0.1% threshold for a rare variant in a gene associated with autosomal dominant familial cerebral cavernous malformations. Absence from large population databases supports pathogenicity at a supporting level. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes/genomes)
- Absent from gnomAD-Canada v1.0 (HostSeq genomes)
Sources
Not met · 24 · evaluated, threshold not reached
PVS1 NM_007217.3:c.345T>G is a missense variant (p.Ser115Arg) in exon 6 of PDCD10. It does not fall into any of the generic PVS1 null-variant buckets — it is neither a nonsense/frameshift variant nor a canonical ±1,2 splice consensus alteration. The ClinGen SVI PVS1 framework (PMC6185798) therefore does not support PVS1 application for this variant class, even though PDCD10 loss of function is an established disease mechanism for familial cerebral cavernous malformations. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Ser115Arg)
- not a predicted null variant
- PVS1 variant assessment confirms variant_bucket=other and apply_generic_pvs1_framework=false
- PDCD10 LoF mechanism supported but not applicable to this missense variant under PVS1
Sources
PS1 No previously established pathogenic variant with the same amino acid change (p.Ser115Arg) at this position has been reported in ClinVar or the literature. This variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no comparator pathogenic variants at Ser115 identified
Sources
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant. No publications describing this variant were identified. Details ▾Hide ▴
Evidence considered
- No de novo data available
- variant not reported in any publication
Still missing
- No family studies or trio sequencing data available
PS3 No well-established functional studies demonstrating a damaging effect for NM_007217.3:c.345T>G (p.Ser115Arg) have been identified. The literature search returned no publications mentioning this variant. The five PDCD10/CCM3 functional papers reviewed describe gene-level LoF effects (siRNA silencing, autophagy defects, DLL4-Notch signaling) but do not test or report this specific missense change. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assays identified in any reviewed publication
- Gene-level CCM3 functional studies (PMID:23388056
- PMID:26417067) do not evaluate p.Ser115Arg
Still missing
- No functional data for this specific missense variant
PS4 No case-control or cohort data demonstrate enrichment of this variant in affected individuals compared to controls. The variant is absent from ClinVar and has not been reported in any publication. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar with no case reports or cohort data
Still missing
- No affected vs. control prevalence data
Sources
PM1 Residue Ser115 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No domain-specific constraint or ClinGen expert-curated domain data are available for PDCD10 to support PM1. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot region
Still missing
- No ClinGen-curated functional domain data for PDCD10
PM5 No comparator missense variants at residue Ser115 have been identified as pathogenic in ClinVar. The PM5 candidate search found zero same-residue candidates. A different pathogenic missense at the same position has not been established. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants identified in ClinVar
Sources
pm5_candidates
PM6 No assumed de novo observation (without confirmed paternity/maternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data of any kind available
Still missing
- No trio or parent-of-origin data
PP1 No cosegregation data with disease in multiple affected family members has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No family studies reporting segregation
PP2 HCI prior probability data is not available for PDCD10. Without quantitative evidence that PDCD10 has a low rate of benign missense variation, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior not found for PDCD10
- No quantitative missense constraint data available
Still missing
- No HCI prior or missense constraint score for PDCD10
PP3 Computational evidence is inconsistent and does not provide multiple lines of support for a deleterious effect. REVEL score is 0.649 (borderline, not strongly pathogenic), BayesDel score is 0.175 (benign range), and SpliceAI predicts no splice impact (max delta = 0.02). The in silico predictions do not converge on a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.649 (borderline
- below typical pathogenic threshold of ~0.75)
- BayesDel: 0.175349 (benign range)
- SpliceAI max delta: 0.02 (no splicing impact predicted)
Sources
PP4 No patient phenotype or family history data are available for this case. PP4 requires a phenotype highly specific for a disease with a single genetic etiology, which cannot be assessed without clinical context. Details ▾Hide ▴
Evidence considered
- No phenotype data provided
Still missing
- No patient phenotype or clinical history available
PP5 No reputable source (ClinVar submitter, clinical laboratory, or publication) has reported this variant as pathogenic. The variant is entirely absent from ClinVar and the published literature. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar with zero submitters
- Variant not reported in any publication
Sources
BA1 The variant is absent from all gnomAD population databases (allele frequency = 0.0), far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0 in gnomAD v2.1
- v4.1
- and gnomAD-Canada
Sources
BS1 The variant is absent from all gnomAD population databases (allele frequency = 0.0), far below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0 in gnomAD v2.1
- v4.1
- and gnomAD-Canada
Sources
BS2 No observation of this variant in a healthy adult individual has been reported. The variant is absent from all population databases and has not been reported in any publication. Details ▾Hide ▴
Evidence considered
- No data on observation in healthy adults
Still missing
- No healthy control data
BS3 No well-established functional studies demonstrating a benign effect for p.Ser115Arg have been identified. While BayesDel (0.175) and SpliceAI (max delta 0.02) suggest no strong deleterious impact, REVEL (0.649) remains in a borderline range, preventing a confident BS3 determination. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assay demonstrating benign effect
- In silico scores are mixed
- not uniformly benign
Still missing
- No functional studies for this variant
Sources
BS4 No segregation data are available to demonstrate lack of segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No cosegregation analysis
BP1 While PDCD10 loss of function is an established mechanism for familial cerebral cavernous malformations, there is insufficient evidence to conclude that primarily truncating variants cause disease to the exclusion of missense variants. The GeneReviews entry and supporting literature describe heterozygous germline pathogenic variants broadly without specifying that missense variants are not a disease mechanism. BP1 cannot be applied without explicit evidence that missense variants in PDCD10 are not pathogenic. Details ▾Hide ▴
Evidence considered
- PDCD10 LoF mechanism confirmed but does not exclude missense pathogenicity
- GeneReviews and literature do not distinguish between truncating and missense mechanisms
Still missing
- No data on benign missense variant rate in PDCD10
Sources
pvs1_gene_context
BP2 No phasing data are available to determine whether this variant has been observed in trans with a pathogenic variant in PDCD10 (autosomal dominant FCCM) or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No phasing or co-occurrence data available
Still missing
- No trans/cis phase data
BP4 Multiple lines of computational evidence do not uniformly suggest no impact. While BayesDel (0.175, benign range) and SpliceAI (max delta 0.02, no splicing impact) are consistent with a benign interpretation, REVEL (0.649) remains in a borderline range that does not confidently exclude a deleterious effect. The evidence is mixed rather than convergent on benign. Details ▾Hide ▴
Evidence considered
- BayesDel 0.175: benign range
- SpliceAI max delta 0.02: no splicing impact
- REVEL 0.649: borderline
- does not clearly support benign effect
Sources
BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available
Still missing
- No cases with alternate molecular basis reported
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar and the published literature. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification reported by any source
Sources
PS5 Not supported by evidence. The variant is not located in a statistically significant mutational hot spot per cancerhotspots.org. No evidence places this residue in a critical functional domain with an absence of benign variation. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant cancer hotspot
- No domain-level constraint data available for this residue
Still missing
- No functional domain constraint data
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant. PDCD10-associated familial cerebral cavernous malformations follow autosomal dominant inheritance. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This variant is a missense substitution that does not alter protein length. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_007217.3:c.345T>G is a missense variant (p.Ser115Arg), not a synonymous change. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PDCD10
- Transcript
- NM_007217.3
- Coding (HGVS c.)
- NM_007217.3:c.345T>G
- Protein (HGVS p.)
- NP_009148.2:p.(Ser115Arg)
- GRCh38
- chr3:167695646 A>C
- GRCh37
- chr3:167413434 A>C
Gene diagram
Every interpreted variant in PDCD10, mapped onto the exon structure of NM_007217.3. Select a row to find it on the plot.
PDCD10NM_007217.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PDCD10
—
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
- 0.649
- BayesDel
- 0.175
How the predictions were used
PP3 Computational evidence is inconsistent and does not provide multiple lines of support for a deleterious effect. REVEL score is 0.649 (borderline, not strongly pathogenic), BayesDel score is 0.175 (benign range), and SpliceAI predicts no splice impact (max delta = 0.02). The in silico predictions do not converge on a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.649 (borderline
- below typical pathogenic threshold of ~0.75)
- BayesDel: 0.175349 (benign range)
- SpliceAI max delta: 0.02 (no splicing impact predicted)
Sources
BP4 Multiple lines of computational evidence do not uniformly suggest no impact. While BayesDel (0.175, benign range) and SpliceAI (max delta 0.02, no splicing impact) are consistent with a benign interpretation, REVEL (0.649) remains in a borderline range that does not confidently exclude a deleterious effect. The evidence is mixed rather than convergent on benign. Details ▾Hide ▴
Evidence considered
- BayesDel 0.175: benign range
- SpliceAI max delta 0.02: no splicing impact
- REVEL 0.649: borderline
- does not clearly support benign effect
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_007217.3:c.345T>G is a missense variant (p.Ser115Arg), not a synonymous change. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.649. BayesDel score = 0.175349.
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 0.020
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_007217.3%3Ac.345T%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-167413434-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-167695646-A-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-167695646-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007217.3%3Ac.345T…
- OncoKB ↗www.oncokb.org/gene/PDCD10/S115R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PDCD10+c.345T%3EG
- 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 = 0.02). REVEL score = 0.649. BayesDel score = 0.175349.
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.