Variant classification summary

NM_000435.2:c.3192A>T

NOTCH3 · NP_000426.2:p.(Glu1064Asp) · NM_000435.2

GRCh37: chr19:15291018 T>A · GRCh38: chr19:15180207 T>A

Gene: NOTCH3 Transcript: NM_000435.2

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

NOTCH3

Transcript

NM_000435.2

Protein

NP_000426.2:p.(Glu1064Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Moderate): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.

2

BP4 (Supporting): REVEL score 0.106 falls in the benign-supporting range (<=0.290), and SpliceAI predicts no splice disruption.

3

Synthesis: one moderate pathogenic and one supporting benign criterion satisfy no Pathogenic or Benign combination rule, so the overall classification is VUS.

Final determination: Generic ACMG/AMP 2015 fallback: PM2(moderate) + BP4(supporting) does not satisfy any P/LP/B/LB combination, so classified as Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: this is a missense variant (p.Glu1064Asp), so no nonsense-mediated decay, truncation, or splice-disruption mechanism is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to establish this amino acid change as a previously reported pathogenic variant.
PS2	Not assessed	Not assessed: no parental genotyping, parentage confirmation, or inheritance data were available to confirm a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay data for this specific variant (p.Glu1064Asp) were identified in the literature.
PS4	Not assessed	Not assessed: no case-control or statistical enrichment data for this variant were available.
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate location in a mutational hotspot or critical functional domain.
PM2	Met	Met (Moderate): the variant is absent from the gnomAD v2.1, v4.1, and gnomAD-Canada population datasets.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: NOTCH3 disease is autosomal dominant, and no second variant in trans was observed, so the recessive-disorder criterion does not apply.
PM4	N/A	Not applicable: this missense variant does not change protein length, so the insertion/deletion premise does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to determine whether this exact amino acid change has been reported pathogenic at this position.
PM6	Not assessed	Not assessed: no parental testing or proband phenotype data were available to establish a presumed de novo occurrence.
PP1	Not assessed	Not assessed: no pedigree, genotype, or segregation data from informative relatives were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate how often benign missense variants occur in this gene.
PP3	Not met	Not met: REVEL score 0.106 is far below the >=0.644 pathogenic threshold, and SpliceAI max delta 0.055 predicts no splice disruption.	revel spliceai
PP4	Not assessed	Not assessed: no phenotype or clinical indication was provided, so a highly specific phenotype could not be established.
PP5	Not met	Not met: no ClinVar record for this exact variant was found, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: the variant is absent from all queried population databases, so no allele frequency reaches the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from all population datasets, so no allele frequency exceeds that expected for a NOTCH3-related disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: the variant is absent from population databases, so no healthy adult carrier or homozygote was observed to assess penetrance.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal protein function for this variant were identified.
BS4	Not assessed	Not assessed: no segregation data from informative unaffected relatives were available.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant's frequency in unaffected controls.
BP2	Not assessed	Not assessed: no co-occurrence data with a pathogenic variant, or phase or phenotype information, were available.
BP3	N/A	Not applicable: this missense variant does not involve a repetitive region, so the in-frame insertion/deletion premise does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): REVEL score 0.106 is within the benign-supporting range (<=0.290), and SpliceAI max delta 0.055 predicts no splice disruption.	revel spliceai
BP5	Not assessed	Not assessed: no phenotype or molecular findings identifying an alternate cause were provided.
BP6	Not met	Not met: no ClinVar record for this exact variant was found, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: this is a missense variant, not a synonymous variant, so the criterion does not apply.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.