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NOTCH3c.5946G>TUncertain significance
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Variant interpretation report

NOTCH3 c.5946G>T, p.(Glu1982Asp)

NM_000435.2:c.5946G>T NP_000426.2:p.(Glu1982Asp) 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

No gene-level summary was recorded for this case.

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

NM_000435.2:c.5946G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Population frequency is 0%, well below the 0.1% PM2 threshold for a rare missense variant in a gene associated with autosomal dominant disease.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no deleterious impact on the gene or gene product. REVEL score is 0.282 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.291 (negative direction, consistent with benign), and SpliceAI predicts no splice alteration (max delta score 0.03). Three independent in silico algorithms using different methodologies all support a benign interpretation.

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 moderate, BP4 supporting benign; combination = 1 moderate + 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.

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000435.2:c.5946G>T (p.Glu1982Asp) is a missense variant in NOTCH3 exon 33 that is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at moderate strength.

Multiple computational predictors (REVEL 0.282, BayesDel -0.291, SpliceAI max delta 0.03) uniformly support a benign effect, meeting BP4 at supporting benign strength.

No other ACMG/AMP criteria are met. The variant is absent from ClinVar, has no reported functional data, and is not located in a known mutational hotspot or critical functional domain. Evidence is insufficient for any classification beyond Variant of Uncertain Significance.

Applying generic ACMG/AMP 2015 combination rules: one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are in conflict. Neither the pathogenic nor benign evidence thresholds are reached, resulting in a classification of Uncertain Significance.

Met · 2

PM2 ModerateNM_000435.2:c.5946G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Population frequency is 0%, well below the 0.1% PM2 threshold for a rare missense variant in a gene associated with autosomal dominant disease. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact on the gene or gene product. REVEL score is 0.282 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.291 (negative direction, consistent with benign), and SpliceAI predicts no splice alteration (max delta score 0.03). Three independent in silico algorithms using different methodologies all support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.282 supports benign.
  • BayesDel -0.291 supports benign.
  • SpliceAI max delta 0.03 predicts no splice impact.
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No same amino acid change (p.Glu1982Asp) has been previously reported as pathogenic in ClinVar or the literature. PS1 requires a previously established pathogenic variant at the same amino acid position with the same change. Details ▾Hide ▴
Evidence considered
  • No ClinVar entries for this variant or for any same-residue comparator at p.Glu1982.
Sources
clinvar ↗
PS2 No de novo observation with confirmed paternity and maternity has been reported for NM_000435.2:c.5946G>T in any literature source. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
PS3 No well-established in vitro or in vivo functional studies have been performed on NM_000435.2:c.5946G>T (p.Glu1982Asp). OncoKB reports unknown oncogenic effect with no variant-specific curated functional data. No publications identified with functional assay data for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies available for this variant. OncoKB classification: Unknown Oncogenic Effect.
Still missing
  • Functional characterization of p.Glu1982Asp has not been performed.
Sources
oncokb ↗
PS4 No case-control or cohort prevalence data are available for NM_000435.2:c.5946G>T. The variant has not been reported in affected individuals in any literature source. Details ▾Hide ▴
Evidence considered
  • No case reports or cohort studies identified for this variant.
Still missing
  • No affected individuals reported.
PM1 NM_000435.2:c.5946G>T (p.Glu1982Asp) does not lie in a statistically significant mutational hotspot per cancerhotspots.org. While NOTCH3 position 1982 resides in the intracellular domain (exon 33), no literature evidence supports this specific residue as a critical functional domain for germline disease. CADASIL-associated pathogenic variants cluster in EGF-like repeats in the extracellular domain, not in the C-terminal intracellular region. Details ▾Hide ▴
Evidence considered
  • Not in a cancerhotspots.org statistically significant hotspot. Position 1982 is in the intracellular domain
  • outside the EGF-repeat region where CADASIL pathogenic variants cluster.
Still missing
  • Domain-level characterization of the NOTCH3 C-terminal intracellular region is not established for germline disease.
PM5 No same-residue comparator variant at p.Glu1982 with a different amino acid change has been classified as pathogenic in ClinVar. Automated PM5 candidate search returned zero candidates. Details ▾Hide ▴
Evidence considered
  • No pathogenic same-residue comparator variants identified at p.Glu1982.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (without confirmed paternity and maternity) has been reported for NM_000435.2:c.5946G>T in any literature source. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
PP1 No co-segregation data are available for NM_000435.2:c.5946G>T. No family studies have been reported. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies reported.
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. NOTCH3 CADASIL is caused by cysteine-altering missense variants in EGF-like repeats. This variant (p.Glu1982Asp, exon 33) is not a cysteine-altering substitution and lies in the intracellular domain, outside the EGF-repeat region where pathogenic missense variants cluster. PP2 cannot be applied without CSPEC/VCEP guidance and specific gene-level missense constraint metrics. Details ▾Hide ▴
Evidence considered
  • Variant is not cysteine-altering and lies outside the EGF-repeat domain where pathogenic NOTCH3 missense variants cluster.
Still missing
  • NOTCH3 missense Z-score and benign missense rate data not available.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.282 (below the 0.5 pathogenic threshold), BayesDel score is -0.291 (negative direction, consistent with benign), and SpliceAI predicts no significant splice impact (max delta score 0.03). All in silico tools point toward a benign or neutral effect rather than a deleterious one. Details ▾Hide ▴
Evidence considered
  • REVEL 0.282 (benign range).
  • BayesDel -0.291 (benign).
  • SpliceAI max delta 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient-specific phenotype or family history information is available for this case. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype provided for assessment.
Still missing
  • Patient phenotype data not available.
PP5 NM_000435.2:c.5946G>T is absent from ClinVar. No reputable source, including expert panels or clinical laboratories, has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗
BA1 NM_000435.2:c.5946G>T is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada). The allele frequency is 0%, far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Population frequency 0% in all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Population frequency is 0% in gnomAD, below the 0.3% BS1 threshold. The variant is too rare in population databases to meet BS1. Details ▾Hide ▴
Evidence considered
  • Population frequency 0% in all gnomAD datasets
  • below 0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 NM_000435.2:c.5946G>T has not been observed in any healthy adult individual in gnomAD or the literature. No data support observation in a healthy individual at an age when disease would be fully penetrant. Details ▾Hide ▴
Evidence considered
  • No observations in healthy individuals.
BS3 No well-established in vitro or in vivo functional studies have demonstrated no damaging effect for NM_000435.2:c.5946G>T. No functional data exist for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies available.
Still missing
  • Functional characterization of p.Glu1982Asp has not been performed.
BS4 No non-segregation data are available for NM_000435.2:c.5946G>T. No family studies have been reported. Details ▾Hide ▴
Evidence considered
  • No family or non-segregation data available.
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants are known to cause disease. NOTCH3 CADASIL is primarily caused by cysteine-altering missense variants, not truncating variants. While NOTCH3 loss-of-function has been reported as a disease modifier in some studies, the predominant established mechanism for CADASIL is missense-mediated. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • NOTCH3 disease mechanism is primarily missense (cysteine-altering)
  • not truncation.
BP2 No observation of NM_000435.2:c.5946G>T in trans with a known pathogenic dominant variant in NOTCH3 has been reported. Details ▾Hide ▴
Evidence considered
  • No in-trans observations reported.
BP5 NM_000435.2:c.5946G>T has not been observed in a case where an alternative molecular basis for disease was identified. No such case has been reported. Details ▾Hide ▴
Evidence considered
  • No observation in a case with an alternate molecular cause.
BP6 NM_000435.2:c.5946G>T is absent from ClinVar. No reputable source, including expert panels or clinical laboratories, has classified this variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗
PS5 No association study or reputable source has established NM_000435.2:c.5946G>T as disease-associated. No CSPEC/VCEP for NOTCH3 exists to provide gene-level guidance. Details ▾Hide ▴
Evidence considered
  • No association data available. No CSPEC/VCEP for NOTCH3.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000435.2:c.5946G>T is a missense variant (p.Glu1982Asp). PVS1 applies only to null variants — nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon-level deletions. This variant does not fall into any of those categories and therefore does not trigger PVS1 assessment under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution p.Glu1982Asp does not qualify as a null variant for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_000435.2:c.5946G>T is a missense variant (p.Glu1982Asp) and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Identifiers

Gene
NOTCH3
Transcript
NM_000435.2
Coding (HGVS c.)
NM_000435.2:c.5946G>T
Protein (HGVS p.)
NP_000426.2:p.(Glu1982Asp)
GRCh38
chr19:15161682 C>A
GRCh37
chr19:15272493 C>A

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 +462 bp
0.000
SpliceAI acceptor gainat -6 bp
0.030
SpliceAI donor lossat +274 bp
0.000
SpliceAI donor gainat +462 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.020

Other predictors

REVEL
0.282
BayesDel
-0.291

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact on the gene or gene product. REVEL score is 0.282 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.291 (negative direction, consistent with benign), and SpliceAI predicts no splice alteration (max delta score 0.03). Three independent in silico algorithms using different methodologies all support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.282 supports benign.
  • BayesDel -0.291 supports benign.
  • SpliceAI max delta 0.03 predicts no splice impact.
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.282 (below the 0.5 pathogenic threshold), BayesDel score is -0.291 (negative direction, consistent with benign), and SpliceAI predicts no significant splice impact (max delta score 0.03). All in silico tools point toward a benign or neutral effect rather than a deleterious one. Details ▾Hide ▴
Evidence considered
  • REVEL 0.282 (benign range).
  • BayesDel -0.291 (benign).
  • SpliceAI max delta 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_000435.2:c.5946G>T is a missense variant (p.Glu1982Asp) and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.282. BayesDel score = -0.291335.

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 0.030 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 = 0.03). REVEL score = 0.282. BayesDel score = -0.291335.

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.