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NOTCH3c.3192A>TUncertain significance
Print report
Variant interpretation report

NOTCH3 c.3192A>T, p.(Glu1064Asp)

NM_000435.2:c.3192A>T NP_000426.2:p.(Glu1064Asp) Missense · exon 20 View identifiers
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.

About NOTCH3

NOTCH3 encodes a transmembrane receptor that relays signals between neighboring cells, helping regulate cell differentiation, growth, and survival. Mutations in NOTCH3 cause CADASIL, an inherited disorder of the small blood vessels in the brain that can lead to strokes, migraines, and progressive cognitive decline. The gene also contributes to cancer: activating mutations or amplifications are found in some leukemias and breast cancers, while inactivating mutations occur in certain solid tumors such as squamous cell carcinomas.

NCBI Gene ↗ OncoKB ↗
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
PM2Moderate
PM2 · moderate

Met (Moderate): the variant is absent from the gnomAD v2.1, v4.1, and gnomAD-Canada population datasets.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met (Supporting): REVEL score 0.106 is within the benign-supporting range (<=0.290), and SpliceAI max delta 0.055 predicts no splice disruption.

Recorded classification: Uncertain significance

Only PM2 (moderate) and BP4 (supporting) were met, which satisfies no ACMG/AMP 2015 Pathogenic or Benign combination rule; the variant is classified as VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
REVEL score
0.106 recorded score

Recorded REVEL score: 0.106. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV105841250, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 5 not met · 16 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

No functional assay evidence (PS3/BS3) exists in the case bundle for this specific NOTCH3 variant; both criteria are not_assessed pending future functional study data.

No ClinGen VCEP/CSPEC exists for NOTCH3 in this case; generic ACMG/AMP 2015 in-silico evidence rules were applied.

REVEL (0.106) and SpliceAI (max delta 0.055) both indicate no pathogenic in-silico signal, so PP3 is not met.

The same REVEL and SpliceAI evidence supports BP4 at default supporting strength under the generic framework.

BayesDel score was available but withheld from both PP3 and BP4 because no verified published calibration threshold is available to this pipeline for BayesDel.

This variant is missense (p.Glu1064Asp), not synonymous, so BP7 is not applicable.

Met · 2

PM2 ModerateMet (Moderate): the variant is absent from the gnomAD v2.1, v4.1, and gnomAD-Canada population datasets. Details ▾Hide ▴
Reasoning

PM2 is met at moderate strength under the generic ACMG/AMP framework: the normalized variant is absent from the queried gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population datasets.

Rule
Generic ACMG/AMP 2015 PM2 (moderate): absent from controls, or at extremely low frequency if recessive.
Evidence considered
  • The normalized GRCh37 representation is 19-15291018-T-A and the GRCh38 representation is 19-15180207-T-A.
  • gnomAD v2.1 (GRCh37), gnomAD v4.1 (GRCh38), and gnomAD-Canada v1.0 (GRCh38) each reported the variant as absent.
  • No applicable NOTCH3 VCEP/CSPEC or local gene-specific framework was retrieved, so generic ACMG/AMP 2015 criterion strength is used.
Still missing
  • The retrieved population records do not provide ancestry-stratified allele numbers or site-coverage metrics; absence should be rechecked if a future dataset returns a low-frequency observation.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMet (Supporting): REVEL score 0.106 is within the benign-supporting range (<=0.290), and SpliceAI max delta 0.055 predicts no splice disruption. Details ▾Hide ▴
Reasoning

Both available calibrated in-silico predictors point toward no deleterious effect for NM_000435.2:c.3192A>T (p.Glu1064Asp), a missense variant with no applicable NOTCH3 VCEP/CSPEC in this case (generic ACMG/AMP framework). REVEL score is 0.106, within the benign-supporting range per the ClinGen SVI-calibrated REVEL thresholds (benign supporting <=0.290; PMID 36413997), consistent with a non-damaging missense prediction. SpliceAI predicts no meaningful splice disruption (max delta score = 0.055, all four delta types <0.06), reinforcing that no computational evidence points to functional impact via splicing. Under generic ACMG/AMP 2015 rules only supporting-strength is applied by default absent a gene-specific framework specifying moderate/strong tiers. BayesDel score is present in the case data but is not used to support BP4 because no verified published calibration threshold/PMID for BayesDel is available to this pipeline.

Evidence considered
  • REVEL score 0.106 for this variant falls within the ClinGen SVI benign-supporting REVEL range (<=0.290), per the REVEL calibration publication (PMID 36413997), supporting a non-damaging missense in-silico prediction for BP4.
  • SpliceAI predicts no significant splice impact for this variant (max delta score = 0.055; DS_AG=0.055, DS_AL=0.014, DS_DG=0.001, DS_DL=0.023), consistent with no splice-altering effect and providing corroborating supporting-strength evidence for BP4.
  • No ClinGen VCEP/CSPEC was found for NOTCH3 in this case (cspec.found=false, framework_mode=generic_acmg), so BP4 is applied at generic ACMG/AMP default supporting strength rather than any gene-specific moderate/strong tier.
  • BayesDel score of -0.429345 was retrieved but is excluded from the BP4 basis because no verified published calibration threshold/PMID for BayesDel is available to this pipeline.
Sources
revelspliceai ↗

Not met · 5 · evaluated, threshold not reached

PP3 Not met: REVEL score 0.106 is far below the >=0.644 pathogenic threshold, and SpliceAI max delta 0.055 predicts no splice disruption. Details ▾Hide ▴
Reasoning

NM_000435.2:c.3192A>T (p.Glu1064Asp) is a missense variant with no applicable ClinGen VCEP/CSPEC for NOTCH3 in this case (framework_mode=generic_acmg, cspec.found=false); generic ACMG/AMP in-silico evaluation therefore applies. REVEL score is 0.106, well below the ClinGen SVI-calibrated pathogenic supporting threshold (>=0.644) established in the REVEL calibration study, so it does not support a damaging prediction. SpliceAI max delta score is 0.055 (DS_AG 0.055, DS_AL 0.014, DS_DG 0.001, DS_DL 0.023), far below the range associated with splice-altering effects, so no splicing-based pathogenic signal is present either. BayesDel score (-0.429345) is available in the case data but is excluded from this assessment because no verified published calibration threshold for BayesDel is available to this pipeline. No component of the in-silico evidence supports a pathogenic prediction, so PP3 is not met.

Evidence considered
  • REVEL score 0.106 for this variant, from local REVEL v1.3 lookup, is below the ClinGen SVI PP3-supporting threshold of >=0.644 for REVEL (Pejaver et al., calibration of computational tools for missense pathogenicity, PMID 36413997), so REVEL does not support PP3.
  • SpliceAI predicts no significant splice impact for this variant (max delta score = 0.055; DS_AG=0.055, DS_AL=0.014, DS_DG=0.001, DS_DL=0.023), consistent with no splice-altering effect and providing no basis for a PP3 splice-impact call.
  • BayesDel score of -0.429345 was retrieved from local BayesDel (170824_noAF) lookup but is treated as not_available for PP3/BP4 purposes because no verified published calibration threshold/PMID for BayesDel is available to this pipeline.
  • No ClinGen VCEP/CSPEC was found for NOTCH3 in this case (cspec.found=false, framework_mode=generic_acmg), so generic ACMG/AMP thresholds apply rather than a gene-specific PP3/BP4 lookup table.
Sources
revelspliceai ↗
PP5 Not met: no ClinVar record for this exact variant was found, so no expert-panel pathogenic assertion exists. Details ▾Hide ▴
Reasoning

PP5 is not met because no exact-variant ClinVar record was retrieved; consequently, there is no exact-variant Pathogenic/Likely pathogenic expert-panel assertion.

Rule
Apply PP5 only to an exact-variant ClinVar Pathogenic or Likely pathogenic classification reviewed by an expert panel; laboratory submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • ClinVar exact-match search for NM_000435.2:c.3192A>T found no result; the bundle states that this variant is absent from ClinVar.
Sources
clinvar ↗
BA1 Not met: the variant is absent from all queried population databases, so no allele frequency reaches the stand-alone benign threshold. Details ▾Hide ▴
Reasoning

BA1 is not met: the variant is absent from the queried gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 datasets, so no population allele frequency reaches a stand-alone benign threshold.

Rule
Generic ACMG/AMP 2015 BA1: allele frequency greater than 5% in population databases is stand-alone benign evidence.
Evidence considered
  • gnomAD v2.1 query for 19-15291018-T-A (GRCh37) returned absent.
  • gnomAD v4.1 query for chr19-15180207-T-A (GRCh38) returned absent.
  • gnomAD-Canada v1.0 query for 19-15180207-T-A (GRCh38) returned absent.
Still missing
  • The retrieved absence records do not provide ancestry-stratified allele numbers or coverage metrics; this does not affect the conclusion that BA1 is not met but limits a quantitative frequency audit.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Not met: the variant is absent from all population datasets, so no allele frequency exceeds that expected for a NOTCH3-related disorder. Details ▾Hide ▴
Reasoning

BS1 is not met: the variant is absent from all queried population datasets and therefore has no allele frequency greater than expected for a NOTCH3-related disorder.

Rule
Generic ACMG/AMP 2015 BS1: an allele frequency greater than expected for the disorder supports a benign interpretation.
Evidence considered
  • gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 each reported this normalized variant as absent.
  • No applicable NOTCH3 VCEP/CSPEC or local gene-specific population-frequency specification was retrieved; generic ACMG/AMP assessment applies.
Still missing
  • No NOTCH3-specific BS1 maximum credible allele-frequency threshold or disease prevalence/penetrance calculation was retrieved because no applicable VCEP or local gene-specific framework was available.
  • The retrieved absence records do not provide ancestry-stratified allele numbers or coverage metrics.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP6 Not met: no ClinVar record for this exact variant was found, so no expert-panel benign assertion exists. Details ▾Hide ▴
Reasoning

BP6 is not met because no exact-variant ClinVar record was retrieved; consequently, there is no exact-variant Benign/Likely benign expert-panel assertion.

Rule
Apply BP6 only to an exact-variant ClinVar Benign or Likely benign classification reviewed by an expert panel; laboratory submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • ClinVar exact-match search for NM_000435.2:c.3192A>T found no result; the bundle states that this variant is absent from ClinVar.
Sources
clinvar ↗

Not assessed · 16 · no assessment recorded

PS1 Not assessed: insufficient evidence was available to establish this amino acid change as a previously reported pathogenic variant. Details ▾Hide ▴
Reasoning

PS1 could not be assessed because its agent did not produce valid output.

Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PS2 Not assessed: no parental genotyping, parentage confirmation, or inheritance data were available to confirm a de novo occurrence. Details ▾Hide ▴
Reasoning

No proband-level phenotype, parental genotyping, parentage confirmation, or inheritance data are available to establish a confirmed de novo occurrence.

Rule
Generic ACMG/AMP 2015: PS2 requires de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed.
Evidence considered
  • No NOTCH3 VCEP/ClinGen gene-specific specification was retrieved; the case designates generic ACMG/AMP fallback.
  • The consolidated case-evidence bundle contains no individual or family-level genotype, parental testing, phenotype, or parentage information for NM_000435.2:c.3192A>T.
Still missing
  • Obtain the proband phenotype and diagnostic indication.
  • Obtain testing results for both biological parents, including the assay and detection limits.
  • Confirm biological parentage if de novo evidence is considered.
PS3 Not assessed: no functional assay data for this specific variant (p.Glu1064Asp) were identified in the literature. Details ▾Hide ▴
Reasoning

No CSPEC/VCEP framework is available for NOTCH3 in this case (cspec.found=false), so generic ACMG applies. No functional/in vitro assay data (splicing assay, minigene, biochemical, cellular, or animal model study) for this specific variant (NM_000435.2:c.3192A>T / p.Glu1064Asp) was identified anywhere in the evidence bundle, literature_packet, or source_registry. The literature_packet explicitly reports total_pmids=0 and 'No PMIDs found across evidence sources.' The PVS1 gene-context literature review surfaced disease-mechanism papers for NOTCH3 generally, but none report a validated functional assay result for this specific variant.

Still missing
  • No published functional/experimental assay data for this exact variant identified in current evidence bundle.
  • No CSPEC/VCEP-specific PS3 assay validation criteria available for NOTCH3.
PS4 Not assessed: no case-control or statistical enrichment data for this variant were available. Details ▾Hide ▴
Reasoning

No case-control or other statistically interpretable enrichment data for NOTCH3 c.3192A>T (p.Glu1064Asp) were retrieved. PS4 cannot be evaluated from population absence, a single somatic COSMIC observation, or gene-level disease knowledge.

Rule
Generic ACMG/AMP 2015 fallback: PS4 requires a statistically increased prevalence of the variant in affected individuals compared with controls.
Evidence considered
  • The consolidated evidence bundle contains no PMID, case series, cohort, or case-control dataset for this exact variant; literature_pass reports no PMIDs retrieved.
  • COSMIC reports one somatic observation only and does not provide germline disease case-control evidence.
Still missing
  • Variant-specific affected-case counts, ancestry-matched control counts, and an appropriate case-control enrichment analysis are unavailable.
PM1 Not assessed: insufficient evidence was available to evaluate location in a mutational hotspot or critical functional domain. Details ▾Hide ▴
Reasoning

PM1 could not be assessed because its agent did not produce valid output.

Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PM5 Not assessed: insufficient evidence was available to determine whether this exact amino acid change has been reported pathogenic at this position. Details ▾Hide ▴
Reasoning

PM5 could not be assessed because its agent did not produce valid output.

Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PM6 Not assessed: no parental testing or proband phenotype data were available to establish a presumed de novo occurrence. Details ▾Hide ▴
Reasoning

No proband-level phenotype or parental testing information is available to establish a presumed de novo occurrence without confirmed parentage.

Rule
Generic ACMG/AMP 2015: PM6 requires a presumed de novo occurrence in a patient with the disease when maternity and paternity are not confirmed.
Evidence considered
  • No NOTCH3 VCEP/ClinGen gene-specific specification was retrieved; the case designates generic ACMG/AMP fallback.
  • The consolidated case-evidence bundle contains no individual or family-level genotype, parental testing, phenotype, or parentage information for NM_000435.2:c.3192A>T.
Still missing
  • Obtain the proband phenotype and diagnostic indication.
  • Obtain testing results for both parents, including whether each parent was tested for the variant.
  • Document whether parentage confirmation was performed.
PP1 Not assessed: no pedigree, genotype, or segregation data from informative relatives were available. Details ▾Hide ▴
Reasoning

No informative affected or unaffected relatives, genotypes, phenotypes, pedigree structure, or meiosis count is available to assess cosegregation.

Rule
Generic ACMG/AMP 2015: PP1 may be applied when the variant cosegregates with disease in multiple affected family members; strength cannot be assigned without family data.
Evidence considered
  • No NOTCH3 VCEP/ClinGen gene-specific specification was retrieved; the case designates generic ACMG/AMP fallback.
  • The consolidated case-evidence bundle contains no family segregation data for NM_000435.2:c.3192A>T.
Still missing
  • Obtain a pedigree with phenotype status and age for informative relatives.
  • Obtain variant testing results for affected and unaffected relatives.
  • Determine the number of informative meioses and account for age-dependent penetrance where relevant.
PP2 Not assessed: insufficient evidence was available to evaluate how often benign missense variants occur in this gene. Details ▾Hide ▴
Reasoning

PP2 could not be assessed because its agent did not produce valid output.

Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PP4 Not assessed: no phenotype or clinical indication was provided, so a highly specific phenotype could not be established. Details ▾Hide ▴
Reasoning

No phenotype, diagnostic work-up, family history, or disease indication for the individual carrying NOTCH3 c.3192A>T was supplied. Therefore, a highly specific phenotype cannot be established for PP4.

Rule
Generic ACMG/AMP 2015 fallback: PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
  • The consolidated evidence bundle contains variant normalization and database results but no patient phenotype or diagnostic findings.
Still missing
  • A detailed phenotype and diagnostic evaluation, including features relevant to the suspected NOTCH3-associated disorder, are required to assess phenotype specificity.
BS2 Not assessed: the variant is absent from population databases, so no healthy adult carrier or homozygote was observed to assess penetrance. Details ▾Hide ▴
Reasoning

BS2 cannot be assessed. The queried population datasets report the variant as absent, so they provide no observation of a healthy adult carrier or homozygote from which to establish lack of penetrance or benignity.

Rule
Generic ACMG/AMP 2015 BS2: observation in a healthy adult individual supports benignity when full penetrance is expected at an early age.
Evidence considered
  • gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 reported the variant as absent; consequently, no carriers or homozygotes were available for BS2 evaluation.
Still missing
  • No data were retrieved documenting this variant in healthy adult individuals, including genotype, age, phenotype, or homozygote count.
  • No NOTCH3-specific BS2 penetrance, age-at-onset, or healthy-homozygote specification was available.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 Not assessed: no functional assay data demonstrating normal protein function for this variant were identified. Details ▾Hide ▴
Reasoning

No CSPEC/VCEP framework is available for NOTCH3 in this case (cspec.found=false), so generic ACMG applies. No functional/in vitro assay data showing normal/benign function for this specific variant (NM_000435.2:c.3192A>T / p.Glu1064Asp) was identified anywhere in the evidence bundle, literature_packet, or source_registry. The literature_packet explicitly reports total_pmids=0 and 'No PMIDs found across evidence sources.'

Still missing
  • No published functional/experimental assay data for this exact variant identified in current evidence bundle.
  • No CSPEC/VCEP-specific BS3 assay validation criteria available for NOTCH3.
BS4 Not assessed: no segregation data from informative unaffected relatives were available. Details ▾Hide ▴
Reasoning

No reliable non-segregation data are available showing the variant in informative unaffected relatives or its absence in affected relatives.

Rule
Generic ACMG/AMP 2015: BS4 requires lack of segregation in affected members of a family; it cannot be assessed without informative family genotypes and phenotypes.
Evidence considered
  • No NOTCH3 VCEP/ClinGen gene-specific specification was retrieved; the case designates generic ACMG/AMP fallback.
  • The consolidated case-evidence bundle contains no family non-segregation data for NM_000435.2:c.3192A>T.
Still missing
  • Obtain a pedigree with phenotype status, age, and relevant clinical evaluation for informative relatives.
  • Obtain variant testing results for affected and unaffected relatives.
  • Evaluate penetrance, phenocopy, and age of onset before interpreting any apparent non-segregation.
BP1 Not assessed: insufficient evidence was available to evaluate the variant's frequency in unaffected controls. Details ▾Hide ▴
Reasoning

BP1 could not be assessed because its agent did not produce valid output.

Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
BP2 Not assessed: no co-occurrence data with a pathogenic variant, or phase or phenotype information, were available. Details ▾Hide ▴
Reasoning

No NOTCH3-specific VCEP specification was retrieved, so generic ACMG/AMP semantics apply. BP2 requires the evaluated variant to be observed in cis with a pathogenic variant for a dominant disorder, or in trans with a pathogenic variant for a recessive disorder, in a manner supporting a benign interpretation. The consolidated evidence provides no individual-level co-occurrence, second-variant classification, phase, phenotype, or segregation data for p.(Glu1064Asp); BP2 cannot be assessed.

Rule
Generic ACMG/AMP BP2: observed in trans with a pathogenic variant for a fully penetrant recessive disorder, or observed in cis with a pathogenic variant for a dominant disorder.
Evidence considered
  • The case bundle reports no NOTCH3 CSPEC/VCEP framework and designates the generic ACMG fallback.
  • No PMIDs were identified in the case literature packet, and the bundle contains no affected-proband, co-occurrence, phase, or segregation record for p.(Glu1064Asp).
  • ClinVar returned no record for the evaluated variant and therefore supplies no submission-level co-occurrence evidence.
Still missing
  • Obtain individual-level co-occurrence data identifying any second NOTCH3 variant, its pathogenic/likely pathogenic evidence, the phenotype of the carrier, and laboratory-confirmed cis/trans phase.
  • For a proposed cis co-occurrence in the dominant CADASIL context, document that both variants are present in an appropriately phenotyped individual and that the observation is informative for benignity.
BP5 Not assessed: no phenotype or molecular findings identifying an alternate cause were provided. Details ▾Hide ▴
Reasoning

No individual-level phenotype or molecular findings identifying an alternate cause for a phenotype were supplied. BP5 cannot be assessed.

Rule
Generic ACMG/AMP 2015 fallback: BP5 requires that a variant be found in a case with an alternate molecular basis for disease.
Evidence considered
  • The consolidated evidence bundle contains no patient-level phenotype, co-occurring molecular diagnosis, or segregation information.
Still missing
  • Individual-level clinical phenotype and testing results are needed to determine whether a separate molecular diagnosis fully explains the phenotype.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: this is a missense variant (p.Glu1064Asp), so no nonsense-mediated decay, truncation, or splice-disruption mechanism is triggered. Details ▾Hide ▴
Reasoning

PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000435.2:c.3192A>T in NOTCH3 is a missense substitution predicted to produce NP_000426.2:p.(Glu1064Asp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_null_variant_class
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM3 N/ANot applicable: NOTCH3 disease is autosomal dominant, and no second variant in trans was observed, so the recessive-disorder criterion does not apply. Details ▾Hide ▴
Reasoning

No NOTCH3-specific VCEP specification was retrieved, so generic ACMG/AMP semantics apply. PM3 requires the variant to be observed in trans with a pathogenic variant in an affected individual for a recessive disorder. The consolidated evidence contains no affected-proband observation of p.(Glu1064Asp), no second germline variant, and no phase information; moreover, the documented NOTCH3 disease context is CADASIL, an autosomal-dominant disorder. PM3 is therefore not applicable to this assessment.

Rule
Generic ACMG/AMP PM3: in recessive disorders, the variant is detected in trans with a pathogenic variant.
Evidence considered
  • The case bundle reports no NOTCH3 CSPEC/VCEP framework and designates the generic ACMG fallback.
  • The case bundle identifies the evaluated variant as NOTCH3 NM_000435.2:c.3192A>T, p.(Glu1064Asp), and reports no variant-associated publications or ClinVar record.
  • The available NOTCH3 disease-context material describes CADASIL as an autosomal-dominant disorder; it does not document this variant in a recessive affected individual with a pathogenic variant in trans.
Still missing
  • No case-level genotype, phase, or affected-proband data were provided.
  • If a recessive NOTCH3 phenotype is specifically under evaluation, obtain phenotype-specific inheritance evidence and confirm trans phase with a pathogenic/likely pathogenic second allele in an affected individual.
PM4 N/ANot applicable: this missense variant does not change protein length, so the insertion/deletion premise does not apply. Details ▾Hide ▴
Reasoning

PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000435.2:c.3192A>T in NOTCH3 is a missense substitution predicted to produce NP_000426.2:p.(Glu1064Asp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP3 N/ANot applicable: this missense variant does not involve a repetitive region, so the in-frame insertion/deletion premise does not apply. Details ▾Hide ▴
Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000435.2:c.3192A>T in NOTCH3 is a missense substitution predicted to produce NP_000426.2:p.(Glu1064Asp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP7 N/ANot applicable: this is a missense variant, not a synonymous variant, so the criterion does not apply. Details ▾Hide ▴
Reasoning

BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000435.2:c.3192A>T in NOTCH3 is a missense substitution predicted to produce NP_000426.2:p.(Glu1064Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Identifiers

Gene
NOTCH3
Transcript
NM_000435.2
Coding (HGVS c.)
NM_000435.2:c.3192A>T
Protein (HGVS p.)
NP_000426.2:p.(Glu1064Asp)
GRCh38
chr19:15180207 T>A
GRCh37
chr19:15291018 T>A
Location and type
Exon 20 · missense
COSMIC
COSV105841250

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…
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

SpliceAI acceptor lossat +49 bp
0.014
SpliceAI acceptor gainat -29 bp
0.055
SpliceAI donor lossat -135 bp
0.023
SpliceAI donor gainat -407 bp
0.001
Pangolin splice lossmagnitude shown
-0.013
Pangolin splice gain
0.005

Other predictors

REVEL
0.106
BayesDel
-0.429

How the predictions were used

BP4 SupportingMet (Supporting): REVEL score 0.106 is within the benign-supporting range (<=0.290), and SpliceAI max delta 0.055 predicts no splice disruption. Details ▾Hide ▴
Reasoning

Both available calibrated in-silico predictors point toward no deleterious effect for NM_000435.2:c.3192A>T (p.Glu1064Asp), a missense variant with no applicable NOTCH3 VCEP/CSPEC in this case (generic ACMG/AMP framework). REVEL score is 0.106, within the benign-supporting range per the ClinGen SVI-calibrated REVEL thresholds (benign supporting <=0.290; PMID 36413997), consistent with a non-damaging missense prediction. SpliceAI predicts no meaningful splice disruption (max delta score = 0.055, all four delta types <0.06), reinforcing that no computational evidence points to functional impact via splicing. Under generic ACMG/AMP 2015 rules only supporting-strength is applied by default absent a gene-specific framework specifying moderate/strong tiers. BayesDel score is present in the case data but is not used to support BP4 because no verified published calibration threshold/PMID for BayesDel is available to this pipeline.

Evidence considered
  • REVEL score 0.106 for this variant falls within the ClinGen SVI benign-supporting REVEL range (<=0.290), per the REVEL calibration publication (PMID 36413997), supporting a non-damaging missense in-silico prediction for BP4.
  • SpliceAI predicts no significant splice impact for this variant (max delta score = 0.055; DS_AG=0.055, DS_AL=0.014, DS_DG=0.001, DS_DL=0.023), consistent with no splice-altering effect and providing corroborating supporting-strength evidence for BP4.
  • No ClinGen VCEP/CSPEC was found for NOTCH3 in this case (cspec.found=false, framework_mode=generic_acmg), so BP4 is applied at generic ACMG/AMP default supporting strength rather than any gene-specific moderate/strong tier.
  • BayesDel score of -0.429345 was retrieved but is excluded from the BP4 basis because no verified published calibration threshold/PMID for BayesDel is available to this pipeline.
Sources
revelspliceai ↗
PP3 Not met: REVEL score 0.106 is far below the >=0.644 pathogenic threshold, and SpliceAI max delta 0.055 predicts no splice disruption. Details ▾Hide ▴
Reasoning

NM_000435.2:c.3192A>T (p.Glu1064Asp) is a missense variant with no applicable ClinGen VCEP/CSPEC for NOTCH3 in this case (framework_mode=generic_acmg, cspec.found=false); generic ACMG/AMP in-silico evaluation therefore applies. REVEL score is 0.106, well below the ClinGen SVI-calibrated pathogenic supporting threshold (>=0.644) established in the REVEL calibration study, so it does not support a damaging prediction. SpliceAI max delta score is 0.055 (DS_AG 0.055, DS_AL 0.014, DS_DG 0.001, DS_DL 0.023), far below the range associated with splice-altering effects, so no splicing-based pathogenic signal is present either. BayesDel score (-0.429345) is available in the case data but is excluded from this assessment because no verified published calibration threshold for BayesDel is available to this pipeline. No component of the in-silico evidence supports a pathogenic prediction, so PP3 is not met.

Evidence considered
  • REVEL score 0.106 for this variant, from local REVEL v1.3 lookup, is below the ClinGen SVI PP3-supporting threshold of >=0.644 for REVEL (Pejaver et al., calibration of computational tools for missense pathogenicity, PMID 36413997), so REVEL does not support PP3.
  • SpliceAI predicts no significant splice impact for this variant (max delta score = 0.055; DS_AG=0.055, DS_AL=0.014, DS_DG=0.001, DS_DL=0.023), consistent with no splice-altering effect and providing no basis for a PP3 splice-impact call.
  • BayesDel score of -0.429345 was retrieved from local BayesDel (170824_noAF) lookup but is treated as not_available for PP3/BP4 purposes because no verified published calibration threshold/PMID for BayesDel is available to this pipeline.
  • No ClinGen VCEP/CSPEC was found for NOTCH3 in this case (cspec.found=false, framework_mode=generic_acmg), so generic ACMG/AMP thresholds apply rather than a gene-specific PP3/BP4 lookup table.
Sources
revelspliceai ↗
BP7 N/ANot applicable: this is a missense variant, not a synonymous variant, so the criterion does not apply. Details ▾Hide ▴
Reasoning

BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000435.2:c.3192A>T in NOTCH3 is a missense substitution predicted to produce NP_000426.2:p.(Glu1064Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.106. BayesDel score = -0.429345.

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 0.055 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

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 = 0.06). REVEL score = 0.106. BayesDel score = -0.429345.

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 previously been reported in somatic cancers (COSMIC; COSV105841250, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.