About NOTCH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH3 c.2299C>A, p.(Arg767Ser)
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
NM_000435.2:c.2299C>A is extremely rare in population databases. The variant is present at a single allele in gnomAD v4.1 (AF = 6.78 × 10⁻⁷; 1/1,475,078 alleles, 0 homozygotes), with its highest subpopulation frequency in European (non-Finnish) at 9.19 × 10⁻⁷ (1/1,088,162). It is absent from gnomAD v2.1 and gnomAD-Canada. This frequency is well below the 0.1% (0.001) PM2 threshold for non-VCEP adjudication.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple independent in silico tools predict a benign effect for NM_000435.2:c.2299C>A (p.Arg767Ser). REVEL score is 0.073 (well below pathogenic threshold), BayesDel score is −0.352 (negative, consistent with benign), and SpliceAI predicts no splice-altering effect (max delta = 0.10). Three concordant benign predictions from independent algorithms satisfy BP4 at supporting benign level.
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
1 / 1,475,078 alleles
gnomAD v4.1: 1 / 1,475,078 alleles. Recorded AF 6.7793e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.100 maximum delta
Recorded SpliceAI maximum delta score: 0.100. 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. NOTCH3 encodes a Type I transmembrane protein of the Notch family. Missense and nonsense mutations in NOTCH3 have been identified in various 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 · 21 not met · 1 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_000435.2:c.2299C>A (p.Arg767Ser) is a missense variant in NOTCH3 with extremely low population frequency (1/1,475,078 alleles in gnomAD v4.1, AF = 6.78e-7), meeting PM2 at supporting level.
Multiple in silico predictors (REVEL 0.073, BayesDel −0.352, SpliceAI max delta 0.10) concordantly predict a benign effect, satisfying BP4 at supporting level.
The variant is absent from ClinVar, COSMIC, and the published literature. No functional studies, segregation data, de novo reports, or same-residue pathogenic comparators are available.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient to classify this variant as either likely pathogenic or likely benign per generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_000435.2:c.2299C>A is extremely rare in population databases. The variant is present at a single allele in gnomAD v4.1 (AF = 6.78 × 10⁻⁷; 1/1,475,078 alleles, 0 homozygotes), with its highest subpopulation frequency in European (non-Finnish) at 9.19 × 10⁻⁷ (1/1,088,162). It is absent from gnomAD v2.1 and gnomAD-Canada. This frequency is well below the 0.1% (0.001) PM2 threshold for non-VCEP adjudication. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1/1
- 475
- 078 alleles
- AF = 6.78e-7
- gnomAD v2.1: absent
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple independent in silico tools predict a benign effect for NM_000435.2:c.2299C>A (p.Arg767Ser). REVEL score is 0.073 (well below pathogenic threshold), BayesDel score is −0.352 (negative, consistent with benign), and SpliceAI predicts no splice-altering effect (max delta = 0.10). Three concordant benign predictions from independent algorithms satisfy BP4 at supporting benign level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.073 (benign-leaning
- below 0.5 threshold)
- BayesDel: -0.352 (negative
- benign prediction)
- SpliceAI max delta: 0.10 (no predicted splice impact)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No alternative nucleotide change at NOTCH3 c.2299 has been reported as pathogenic in ClinVar or the literature. This variant is entirely absent from ClinVar, precluding any same-nucleotide pathogenic comparator. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no alternate nucleotide at c.2299 is classified as pathogenic
Sources
PS2 No de novo observation with confirmed maternity and paternity has been reported for NM_000435.2:c.2299C>A. Details ▾Hide ▴
Still missing
- No de novo study data available for this variant
PS3 No functional or experimental studies testing NM_000435.2:c.2299C>A (p.Arg767Ser) were identified. OncoKB reports no variant-specific functional evidence. The literature pass returned zero PMIDs for this variant. In the absence of any direct experimental or systematic-range functional characterization, PS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
- No PMIDs identified in literature review for this variant
Still missing
- No functional studies available for p.Arg767Ser or a systematically characterized range encompassing this position
Sources
PS4 No case-control studies demonstrating statistically higher prevalence of NM_000435.2:c.2299C>A in affected individuals compared to controls are available. Details ▾Hide ▴
Still missing
- No case-control data for this variant
PM1 Residue Arg767 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No variant-specific domain-level functional evidence was identified to support PM1. While this position lies within the NOTCH3 extracellular EGF-like repeat region, the variant is not cysteine-altering and there is no specific literature evidence demonstrating that p.Arg767Ser disrupts a critical functional domain. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue Arg767 is not a statistically significant hotspot
- Variant is not cysteine-altering (Arg→Ser)
- unlike classic CADASIL-associated mutations
Still missing
- No domain-specific functional characterization for residue 767
Sources
PM5 No pathogenic missense variant at the same amino acid residue (Arg767) has been identified in ClinVar. The PM5 candidate search returned zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue pathogenic variants found
- ClinVar: absent for all NOTCH3 variants at codon 767
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (maternity and paternity unconfirmed) has been reported for NM_000435.2:c.2299C>A. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No cosegregation data with disease in multiple affected family members is available for NM_000435.2:c.2299C>A. Details ▾Hide ▴
Still missing
- No family cosegregation data
PP3 Multiple in silico tools predict a benign effect for NM_000435.2:c.2299C>A (p.Arg767Ser). REVEL score is 0.073 (well below the 0.5 threshold for pathogenicity), BayesDel score is −0.352 (negative, indicating benign), and SpliceAI predicts no splice impact (max delta = 0.10). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.073 (benign-leaning)
- BayesDel: -0.352 (benign)
- SpliceAI max delta: 0.10 (no splice impact)
Sources
PP4 No detailed patient phenotype or family history data are available to assess whether the phenotype is highly specific for NOTCH3-related disease. Details ▾Hide ▴
Still missing
- No patient phenotype data available
PP5 NM_000435.2:c.2299C>A is absent from ClinVar and has not been reported as pathogenic by any reputable clinical diagnostic laboratory or expert panel. Details ▾Hide ▴
BA1 The allele frequency in gnomAD v4.1 is 6.78 × 10⁻⁷ (0.00007%), far below the 1% BA1 threshold. This variant is not a common polymorphism. Details ▾Hide ▴
BS1 The allele frequency in gnomAD v4.1 (AF = 6.78 × 10⁻⁷, highest in NFE at 9.19 × 10⁻⁷) is far below the 0.3% non-VCEP BS1 threshold. This rare frequency does not exceed what would be expected for a NOTCH3 disease-causing variant. Details ▾Hide ▴
BS2 While a single allele is observed in gnomAD v4.1, there is no confirmatory evidence that this carrier is an unaffected healthy adult, and a single observation is insufficient to meet BS2 requirements for a dominant disorder. Details ▾Hide ▴
Evidence considered
- 1 allele in gnomAD v4.1
- insufficient for BS2 in dominant disease
Still missing
- No healthy adult confirmation for the single gnomAD carrier
Sources
BS3 No functional or experimental studies demonstrating that NM_000435.2:c.2299C>A (p.Arg767Ser) has no damaging effect on protein function or splicing have been identified. The in silico benign predictions (REVEL 0.073, BayesDel −0.352) are computational, not experimental, and do not satisfy BS3's requirement for functional assay evidence. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant
- In silico scores are computational
- not functional evidence
Still missing
- No functional studies demonstrating no damaging effect
Sources
BS4 No family studies demonstrating lack of segregation of NM_000435.2:c.2299C>A with disease are available. Details ▾Hide ▴
Still missing
- No segregation data available
BP1 BP1 applies when a missense variant is found in a gene where only truncating variants cause disease. For NOTCH3, CADASIL is predominantly caused by missense variants (cysteine-altering) in the EGF-like repeat domains, not exclusively by truncating variants. Additionally, the PVS1 gene context confirms that NOTCH3 loss-of-function is a supported disease mechanism, not the sole mechanism. Details ▾Hide ▴
Evidence considered
- NOTCH3 CADASIL is predominantly a missense disease (cysteine-altering variants)
- Truncating variants are not the exclusive disease mechanism
Sources
pvs1_gene_context
BP2 No data are available to determine whether NM_000435.2:c.2299C>A has been observed in trans with a known pathogenic NOTCH3 variant in a case of recessive disease. Details ▾Hide ▴
Still missing
- No trans-phase observation data available
BP5 No data are available demonstrating that NM_000435.2:c.2299C>A is found in a case with an alternate established molecular basis for disease. Details ▾Hide ▴
Still missing
- No data on alternate molecular basis in carriers
BP6 NM_000435.2:c.2299C>A is absent from ClinVar and has not been reported as benign by any reputable clinical diagnostic laboratory or expert panel. Details ▾Hide ▴
PS5 No family studies demonstrating segregation of NM_000435.2:c.2299C>A with disease have been reported. Details ▾Hide ▴
Still missing
- No segregation data available
Not assessed · 1 · no assessment recorded
PP2 PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism. While NOTCH3 CADASIL is predominantly caused by missense variants (cysteine-altering), no gene-level missense constraint metrics (e.g., Z-score, missense o/e ratio) are available in the evidence brief to support application of PP2. Details ▾Hide ▴
Still missing
- No gnomAD missense constraint data (Z-score
- o/e) in evidence brief
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000435.2:c.2299C>A is a missense variant (p.Arg767Ser); it does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is reserved for loss-of-function null variants. Details ▾Hide ▴
Evidence considered
- Variant class: substitution (missense)
- Not a nonsense
- frameshift
- or canonical splice site variant
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/ANOTCH3-related CADASIL is an autosomal dominant disorder; PM3 applies only to recessive disorders where a variant is detected in trans with a pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANM_000435.2:c.2299C>A is a single-nucleotide missense substitution; PM4 applies only to in-frame deletions/insertions, stop-loss variants, or initiation codon changes. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ANM_000435.2:c.2299C>A is a missense substitution; BP3 applies only to in-frame insertions or deletions in repetitive regions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_000435.2:c.2299C>A is a missense variant (p.Arg767Ser), not a synonymous (silent) variant. BP7 is reserved for synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NOTCH3
- Transcript
- NM_000435.2
- Coding (HGVS c.)
- NM_000435.2:c.2299C>A
- Protein (HGVS p.)
- NP_000426.2:p.(Arg767Ser)
- GRCh38
- chr19:15185017 G>T
- GRCh37
- chr19:15295828 G>T
Gene diagram
Every interpreted variant in NOTCH3, mapped onto the exon structure of NM_000435.2. Select a row to find it on the plot.
NOTCH3NM_000435.2
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 NOTCH3
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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
1 / 1,475,078 alleles
AF 6.78e-07 · 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 6.8e-07 · 1 / 1,475,078 alleles · 0 hom
| European (non-Finnish)1 / 1,088,162 | 9.2e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.7793e-07; MAF= 0.00007%, 1/1475078 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.18981e-07; MAF= 0.00009%, 1/1088162 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
- 0.073
- BayesDel
- -0.352
How the predictions were used
BP4 SupportingMultiple independent in silico tools predict a benign effect for NM_000435.2:c.2299C>A (p.Arg767Ser). REVEL score is 0.073 (well below pathogenic threshold), BayesDel score is −0.352 (negative, consistent with benign), and SpliceAI predicts no splice-altering effect (max delta = 0.10). Three concordant benign predictions from independent algorithms satisfy BP4 at supporting benign level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.073 (benign-leaning
- below 0.5 threshold)
- BayesDel: -0.352 (negative
- benign prediction)
- SpliceAI max delta: 0.10 (no predicted splice impact)
Sources
PP3 Multiple in silico tools predict a benign effect for NM_000435.2:c.2299C>A (p.Arg767Ser). REVEL score is 0.073 (well below the 0.5 threshold for pathogenicity), BayesDel score is −0.352 (negative, indicating benign), and SpliceAI predicts no splice impact (max delta = 0.10). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.073 (benign-leaning)
- BayesDel: -0.352 (benign)
- SpliceAI max delta: 0.10 (no splice impact)
Sources
BP7 N/ANM_000435.2:c.2299C>A is a missense variant (p.Arg767Ser), not a synonymous (silent) variant. BP7 is reserved for synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.073. BayesDel score = -0.351535.
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
1 / 1,475,078 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.100
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_000435.2%3Ac.2299C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-15295828-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-15185017-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-15185017-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000435.2%3Ac.2299…
- OncoKB ↗www.oncokb.org/gene/NOTCH3/R767S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NOTCH3+c.2299C%3EA
- 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= 6.7793e-07; MAF= 0.00007%, 1/1475078 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.18981e-07; MAF= 0.00009%, 1/1088162 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 = 0.10). REVEL score = 0.073. BayesDel score = -0.351535.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NOTCH3 encodes a Type I transmembrane protein of the Notch family. Missense and nonsense mutations in NOTCH3 have been identified in various 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.