0%
NOTCH3c.3257A>CUncertain significance
Print report
Variant interpretation report

NOTCH3 c.3257A>C, p.(Asp1086Ala)

NM_000435.2:c.3257A>C NP_000426.2:p.(Asp1086Ala) 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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.0%), meeting PM2 threshold of <0.1% allele frequency.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

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

SpliceAI score
0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
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: 1 met · 7 not met · 15 not assessed · 3 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.3257A>C (p.Asp1086Ala) is a missense variant in NOTCH3 exon 20. This variant is absent from large population databases (gnomAD v2.1, v4.1, and gnomAD-Canada; PM2_supporting). No pathogenic or benign criteria beyond PM2_supporting are met. The variant is not cysteine-altering and lies outside known mutational hotspots. No functional, segregation, de novo, case-control, or clinical classification data are available. Based on ACMG/AMP 2015 generic classification rules (PMID:25741868), a single supporting pathogenic criterion (PM2_supporting) is insufficient to reach Likely Pathogenic or any other classification tier. This variant is classified as a Variant of Uncertain Significance (VUS).

Met · 1

PM2 SupportingThis variant is absent from large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.0%), meeting PM2 threshold of <0.1% allele frequency. 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 ↗

Not met · 7 · evaluated, threshold not reached

PM1 Residue Asp1086 is not located in a statistically significant mutational hotspot (Cancer Hotspots: not significant). The variant does not alter a cysteine residue within an EGF-like repeat domain, which is the hallmark pathogenic mechanism in NOTCH3-associated CADASIL. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots reports residue 1086 is not statistically significant for mutation clustering
  • variant is Asp1086Ala
  • not cysteine-altering
PP2 The variant is a non-cysteine missense change (Asp1086Ala) in NOTCH3. Although NOTCH3 missense variants cause CADASIL, the established disease mechanism is specifically cysteine-altering variants within EGF-like repeat domains. HCI prior constraint data is not available for NOTCH3 to assess the gene's benign missense variation rate. Insufficient evidence to support PP2. Details ▾Hide ▴
Evidence considered
  • Variant is Asp1086Ala
  • not cysteine-altering
  • NOTCH3 CADASIL mechanism is cysteine-dependent
  • HCI prior not available
Still missing
  • HCI prior constraint score not available for NOTCH3
PP3 REVEL score of 0.744 is borderline but not supported by BayesDel (0.07, below deleterious threshold). SpliceAI predicts no splice impact (max delta 0.05). Insufficient multi-tool computational consensus to support a deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.744 (borderline deleterious)
  • BayesDel: 0.0698 (below deleterious threshold)
  • SpliceAI max delta: 0.05 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0%). Does not meet BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0% across all gnomAD datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0%). Does not meet BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0% across all gnomAD datasets
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP1 NOTCH3-associated disease (CADASIL) is primarily caused by missense variants, not truncating variants. BP1 is not applicable for genes where missense variants are the predominant disease mechanism. Details ▾Hide ▴
Evidence considered
  • CADASIL is caused predominantly by missense variants in NOTCH3
  • not truncating variants
BP4 REVEL score of 0.744 is above 0.5, indicating a prediction of deleterious effect. Computational evidence does not support no impact on gene product, and therefore BP4 is not met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.744 (suggests deleterious effect
  • not benign)
Sources
revelbayesdelspliceai ↗

Not assessed · 15 · no assessment recorded

PS1 No previously established pathogenic variant at amino acid residue 1086 has been identified in ClinVar or the literature to support PS1. Details ▾Hide ▴
Still missing
  • No ClinVar records or literature reports of a different pathogenic missense change at Asp1086
PS2 No de novo evidence with both maternity and paternity confirmed is available in ClinVar or the literature for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports available
PS3 No variant-specific functional evidence (in vitro or in vivo) demonstrating a damaging effect is available in the literature, ClinVar, or OncoKB curated sources. Details ▾Hide ▴
Still missing
  • No functional studies for this variant identified
PS4 No case-control or prevalence data comparing affected vs. unaffected individuals are available for this variant. Details ▾Hide ▴
Still missing
  • No case-control or cohort studies identified for this variant
PM6 No de novo evidence without confirmed paternity/maternity is available in ClinVar or the literature for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports available
PP1 No cosegregation data with disease in multiple affected family members are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No phenotype or family history data specific to this variant are available to assess whether the patient's presentation is highly specific for NOTCH3-related disease. Details ▾Hide ▴
Still missing
  • No clinical phenotype or family history data provided
PP5 This variant is absent from ClinVar; no reputable source has classified it as pathogenic. Details ▾Hide ▴
Still missing
  • Variant absent from ClinVar
BS2 No evidence of observation in a healthy adult individual in trans with a known pathogenic NOTCH3 variant is available. Details ▾Hide ▴
Still missing
  • No trans-configuration data available
BS3 No variant-specific functional studies (in vitro or in vivo) demonstrating no damaging effect are available in the literature, ClinVar, or OncoKB. Details ▾Hide ▴
Still missing
  • No functional studies for this variant identified
BS4 No family segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No evidence of observation in trans with a known dominant pathogenic NOTCH3 variant is available. Details ▾Hide ▴
Still missing
  • No trans-configuration data available
BP5 No evidence of an alternate molecular basis for disease in a case carrying this variant is available. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data available
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign. Details ▾Hide ▴
Still missing
  • Variant absent from ClinVar
PS5 No de novo evidence without confirmed maternity/paternity is available in ClinVar or the literature for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports available
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (p.Asp1086Ala); does not fall into PVS1 null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework does not apply. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a null variant
Sources
pvs1_generic_framework ↗
PM5 N/ANo same-residue comparator missense variant with established pathogenicity was identified in ClinVar or literature; PM5 candidate harvesting returned no candidates. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AVariant is a missense substitution (c.3257A>C, p.Asp1086Ala), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
NOTCH3
Transcript
NM_000435.2
Coding (HGVS c.)
NM_000435.2:c.3257A>C
Protein (HGVS p.)
NP_000426.2:p.(Asp1086Ala)
GRCh38
chr19:15180142 T>G
GRCh37
chr19:15290953 T>G

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 +114 bp
0.020
SpliceAI acceptor gainat -269 bp
0.000
SpliceAI donor lossat -70 bp
0.050
SpliceAI donor gainat +16 bp
0.010
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.000

Other predictors

REVEL
0.744
BayesDel
0.070

How the predictions were used

PP3 REVEL score of 0.744 is borderline but not supported by BayesDel (0.07, below deleterious threshold). SpliceAI predicts no splice impact (max delta 0.05). Insufficient multi-tool computational consensus to support a deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.744 (borderline deleterious)
  • BayesDel: 0.0698 (below deleterious threshold)
  • SpliceAI max delta: 0.05 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.744 is above 0.5, indicating a prediction of deleterious effect. Computational evidence does not support no impact on gene product, and therefore BP4 is not met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.744 (suggests deleterious effect
  • not benign)
Sources
revelbayesdelspliceai ↗
BP7 N/AVariant is a missense substitution (c.3257A>C, p.Asp1086Ala), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.744. BayesDel score = 0.0697656.

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 0.050 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 = 0.05). REVEL score = 0.744. BayesDel score = 0.0697656.

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.