About NOTCH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NOTCH3 c.3452G>A, p.(Gly1151Glu)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at an ultra-rare allele frequency of 1.24e-6 (2/1,614,098 alleles, 0 homozygotes), well below the 0.1% PM2 threshold for non-VCEP adjudication.
PP3Supporting
PP3 · supporting
REVEL predicts a damaging effect with a score of 0.866 (above the 0.5 threshold). BayesDel score of 0.474 is borderline. SpliceAI reports no significant splice impact (max delta 0.02). At least one in silico predictor (REVEL) supports a deleterious effect on the gene product, meeting supporting-level PP3.
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, PP3 supporting; combination = 2 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
2 / 1,614,098 alleles
gnomAD v4.1: 2 / 1,614,098 alleles. Recorded AF 1.23908e-06. Recorded homozygote count 0.
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.
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 · 20 not met · 1 not assessed · 6 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.3452G>A (p.Gly1151Glu) is a missense variant in NOTCH3, a gene in which missense variants are a well-established cause of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).
This variant is ultra-rare in population databases, absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 1.24e-6 (2/1,614,098 alleles, 0 homozygotes), well below the 0.1% PM2 threshold (PM2_Supporting).
In silico analysis with REVEL yields a score of 0.866, predicting a damaging effect on the protein. BayesDel is borderline at 0.474, and SpliceAI predicts no splice impact (max delta 0.02) (PP3_Supporting).
No variant-specific functional data, de novo observations, case-control studies, segregation data, or ClinVar classifications are available for this variant. The variant is absent from ClinVar and has not been reported in COSMIC or literature.
With only two supporting-level pathogenic criteria (PM2_Supporting, PP3_Supporting) and no benign criteria met, the evidence is insufficient to classify this variant as pathogenic, likely pathogenic, benign, or likely benign under the ACMG/AMP 2015 framework. This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at an ultra-rare allele frequency of 1.24e-6 (2/1,614,098 alleles, 0 homozygotes), well below the 0.1% PM2 threshold for non-VCEP adjudication. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: AF=1.24e-6 (2/1
- 614
- 098 alleles
- 0 homozygotes).
Sources
PP3 SupportingREVEL predicts a damaging effect with a score of 0.866 (above the 0.5 threshold). BayesDel score of 0.474 is borderline. SpliceAI reports no significant splice impact (max delta 0.02). At least one in silico predictor (REVEL) supports a deleterious effect on the gene product, meeting supporting-level PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.866 (damaging). BayesDel: 0.474 (borderline
- below 0.5). SpliceAI: max delta 0.02 (no splice impact).
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No prior pathogenic variant resulting in the same amino acid change (p.Gly1151Glu) has been reported in ClinVar or the literature. There is no evidence that the same nucleotide change has been previously established as pathogenic. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar. No PMIDs with variant-specific evidence were identified.
Sources
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available in case materials or literature.
Still missing
- De novo status unknown
- no parental testing data provided.
PS3 No variant-specific functional data are available for p.Gly1151Glu. OncoKB classifies this variant as having unknown oncogenic effect. No publications with functional characterization of this variant or a systematically characterized range that includes residue 1151 were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No functional studies identified in literature. No saturation mutagenesis or systematic range characterization covering residue 1151.
Still missing
- Functional characterization of p.Gly1151Glu has not been performed.
Sources
PS4 No case-control studies or prevalence data in affected individuals versus controls are available for this variant. Details ▾Hide ▴
Evidence considered
- No affected vs. control prevalence data available for this variant.
Still missing
- Variant prevalence in affected populations is unknown.
PM1 Residue G1151 is not located within a statistically significant mutational hotspot as determined by cancerhotspots.org. While NOTCH3 has well-characterized EGF-like repeat domains where pathogenic cysteine-altering variants cluster in CADASIL, G1151E is a glycine-to-glutamate change, not a cysteine-altering variant, and no domain-level functional data specific to this region were identified in the case materials that would independently support PM1. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant. No domain-level functional characterization spanning residue 1151 identified. G1151E is not a cysteine-altering variant.
Sources
PM5 No same-residue comparator variant (different missense change at p.Gly1151) with an established pathogenic classification was identified. The automated PM5 candidate search returned no candidates. Details ▾Hide ▴
Evidence considered
- pm5_candidates: found=false
- 0 same-residue candidates. ClinVar: absent for all NOTCH3 residue 1151 variants.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (without confirmation of paternity and maternity) has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- De novo status unknown.
PP1 No co-segregation data with disease in multiple affected family members are available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- Segregation analysis has not been performed.
PP4 No patient phenotype or clinical data are available to assess whether the phenotype is highly specific for NOTCH3-related disease. Details ▾Hide ▴
Evidence considered
- No proband phenotype information available.
Still missing
- Patient phenotype data not provided.
PP5 This variant is absent from ClinVar. No reputable source has classified this variant as pathogenic. The ClinVar global PP5/BP6 override rule (ClinVar 3-star expert panel → supporting) does not apply as no ClinVar entry exists. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no entries
- no classifications
- no expert panel reviews.
Sources
BA1 The allele frequency in gnomAD v4.1 is 1.24e-6 (0.000124%), far below the 1% BA1 threshold. This variant is ultra-rare, not common. Details ▾Hide ▴
BS1 The allele frequency in gnomAD v4.1 is 1.24e-6, far below the 0.3% BS1 threshold for non-VCEP adjudication. Details ▾Hide ▴
BS2 No evidence that this variant has been observed in healthy adults at an age when full penetrance of NOTCH3-related disease would be expected. Details ▾Hide ▴
Evidence considered
- No observation in healthy adults with expected full penetrance.
Still missing
- Healthy adult carrier data not available.
BS3 No well-established functional studies demonstrating no damaging effect on protein function or splicing are available for this variant. OncoKB reports unknown oncogenic effect; no publications report benign functional characterization. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No functional studies demonstrating benign effect identified.
Still missing
- Functional characterization to rule out damaging effect has not been performed.
Sources
BS4 No segregation data in affected families are available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- Segregation analysis not performed.
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. CADASIL is primarily caused by missense (cysteine-altering) variants in NOTCH3, not truncating variants. BP1 does not apply. Details ▾Hide ▴
Evidence considered
- NOTCH3 disease mechanism (CADASIL) is primarily missense (cysteine-altering)
- not truncating.
BP2 No observation of this variant in trans with a known pathogenic variant in a gene associated with a fully penetrant dominant disorder has been reported. Details ▾Hide ▴
Evidence considered
- No trans observation with pathogenic variant reported.
BP4 REVEL predicts a damaging effect with a score of 0.866, contradicting benign in silico predictions. BayesDel score of 0.474 is borderline. The SpliceAI max delta score of 0.02 indicates no splice impact, but this alone is insufficient to meet BP4 when a primary pathogenicity predictor (REVEL) indicates a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.866 (damaging) — contradicts BP4. SpliceAI: 0.02 (no splice impact). BayesDel: 0.474 (borderline).
Sources
BP5 No case has been reported where an alternative molecular basis for disease was identified in an individual carrying this variant, which would suggest the variant is not causative. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis reported for individuals with this variant.
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign. The ClinVar global PP5/BP6 override rule (ClinVar 3-star expert panel → supporting benign) does not apply as no ClinVar entry exists. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no entries
- no classifications
- no expert panel reviews.
Sources
Not assessed · 1 · no assessment recorded
PP2 PP2 requires demonstration that the gene has a low rate of benign missense variation (typically via a high missense Z-score) in a gene where missense variants are a common mechanism of disease. While NOTCH3 missense variants are a well-established mechanism in CADASIL, the missense constraint metric (Z-score) for NOTCH3 was not available in the provided evidence materials, precluding a definitive PP2 assessment. Details ▾Hide ▴
Evidence considered
- NOTCH3 missense variants cause CADASIL
- but no missense Z-score or constraint data were available.
Still missing
- NOTCH3 missense Z-score / gnomAD constraint metrics not available in case materials.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant (NM_000435.2:c.3452G>A, p.Gly1151Glu) is a missense substitution and does not fall into any ClinGen PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus variants). The generic PVS1 framework is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (G>A at c.3452)
- classified as variant_bucket='other' by PVS1 variant assessment.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 is reserved for recessive disorders where the variant is observed in trans with a pathogenic variant. NOTCH3-associated CADASIL is an autosomal dominant disorder. Details ▾Hide ▴
Evidence considered
- NOTCH3 CADASIL is autosomal dominant
- PM3 is for recessive disorders.
PM4 N/APM4 applies to protein-length-altering variants (non-frameshift indels, stop-loss, initiation codon). This is a missense substitution that does not alter protein length. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- does not alter protein length.
BP3 N/ABP3 applies to in-frame insertions or deletions in repetitive regions. This is a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame indel.
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact. This variant (c.3452G>A, p.Gly1151Glu) is a missense substitution, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Gly1151Glu)
- not synonymous. SpliceAI max delta 0.02 (no splice impact).
Sources
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. In the canonical Richards et al. 2015 framework, same-residue different missense change is assessed under PM5. This criterion is not applicable under the generic ACMG/AMP framework used for this case. Details ▾Hide ▴
Evidence considered
- PS5 does not exist in the ACMG/AMP 2015 classification framework.
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- NOTCH3
- Transcript
- NM_000435.2
- Coding (HGVS c.)
- NM_000435.2:c.3452G>A
- Protein (HGVS p.)
- NP_000426.2:p.(Gly1151Glu)
- GRCh38
- chr19:15179372 C>T
- GRCh37
- chr19:15290183 C>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
2 / 1,614,098 alleles
AF 1.24e-06 · 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 1.2e-06 · 2 / 1,614,098 alleles · 0 hom
| Remaining individuals1 / 62,508 | 1.6e-05 |
| European (non-Finnish)1 / 1,180,042 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: 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= 1.23908e-06; MAF= 0.00012%, 2/1614098 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.5998e-05; MAF= 0.00160%, 1/62508 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
- 0.866
- BayesDel
- 0.474
How the predictions were used
PP3 SupportingREVEL predicts a damaging effect with a score of 0.866 (above the 0.5 threshold). BayesDel score of 0.474 is borderline. SpliceAI reports no significant splice impact (max delta 0.02). At least one in silico predictor (REVEL) supports a deleterious effect on the gene product, meeting supporting-level PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.866 (damaging). BayesDel: 0.474 (borderline
- below 0.5). SpliceAI: max delta 0.02 (no splice impact).
Sources
BP4 REVEL predicts a damaging effect with a score of 0.866, contradicting benign in silico predictions. BayesDel score of 0.474 is borderline. The SpliceAI max delta score of 0.02 indicates no splice impact, but this alone is insufficient to meet BP4 when a primary pathogenicity predictor (REVEL) indicates a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.866 (damaging) — contradicts BP4. SpliceAI: 0.02 (no splice impact). BayesDel: 0.474 (borderline).
Sources
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact. This variant (c.3452G>A, p.Gly1151Glu) is a missense substitution, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Gly1151Glu)
- not synonymous. SpliceAI max delta 0.02 (no splice impact).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.866. BayesDel score = 0.47403.
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
2 / 1,614,098 recorded alleles
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 ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000435.2%3Ac.3452G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-15290183-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-15179372-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-15179372-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000435.2%3Ac.3452…
- OncoKB ↗www.oncokb.org/gene/NOTCH3/G1151E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NOTCH3+c.3452G%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= 1.23908e-06; MAF= 0.00012%, 2/1614098 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.5998e-05; MAF= 0.00160%, 1/62508 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 = 0.02). REVEL score = 0.866. BayesDel score = 0.47403.
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.