rs559917218
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP2PP3BP4_StrongBP6BS2
The NM_017617.5(NOTCH1):c.2495C>T(p.Pro832Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,396 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00037 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
NOTCH1
NM_017617.5 missense
NM_017617.5 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 9.37
Genes affected
NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.053106725).
BP6
Variant 9-136511244-G-A is Benign according to our data. Variant chr9-136511244-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134918.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, not_provided=1}.
BS2
High AC in GnomAd4 at 56 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.2495C>T | p.Pro832Leu | missense_variant | 16/34 | ENST00000651671.1 | NP_060087.3 | |
LOC124902310 | XR_007061865.1 | n.507+1265G>A | intron_variant, non_coding_transcript_variant | |||||
NOTCH1 | XM_011518717.3 | c.1772C>T | p.Pro591Leu | missense_variant | 13/31 | XP_011517019.2 | ||
LOC124902310 | XR_007061864.1 | n.722G>A | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.2495C>T | p.Pro832Leu | missense_variant | 16/34 | NM_017617.5 | ENSP00000498587 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000368 AC: 56AN: 152138Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000536 AC: 132AN: 246062Hom.: 0 AF XY: 0.000417 AC XY: 56AN XY: 134434
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GnomAD4 exome AF: 0.000149 AC: 218AN: 1460140Hom.: 0 Cov.: 33 AF XY: 0.000139 AC XY: 101AN XY: 726374
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GnomAD4 genome AF: 0.000368 AC: 56AN: 152256Hom.: 1 Cov.: 33 AF XY: 0.000511 AC XY: 38AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 21, 2023 | - - |
Aortic valve disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 31, 2019 | - - |
NOTCH1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 09, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 01, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2020 | - - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at