rs201620358
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_017617.5(NOTCH1):c.2734C>T(p.Arg912Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,605,840 control chromosomes in the GnomAD database, including 8 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 0.0022 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0027 ( 8 hom. )
Consequence
NOTCH1
NM_017617.5 missense
NM_017617.5 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 2.57
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 -11 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.105588555).
BP6
Variant 9-136510659-G-A is Benign according to our data. Variant chr9-136510659-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134921.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=3, Likely_benign=4, not_provided=1}. Variant chr9-136510659-G-A is described in Lovd as [Likely_benign]. Variant chr9-136510659-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00219 (333/152362) while in subpopulation NFE AF= 0.00345 (235/68028). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High AC in GnomAd4 at 333 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.2734C>T | p.Arg912Trp | missense_variant | Exon 17 of 34 | ENST00000651671.1 | NP_060087.3 | |
NOTCH1 | XM_011518717.3 | c.2011C>T | p.Arg671Trp | missense_variant | Exon 14 of 31 | XP_011517019.2 | ||
LOC124902310 | XR_007061864.1 | n.508-371G>A | intron_variant | Intron 1 of 1 | ||||
LOC124902310 | XR_007061865.1 | n.507+680G>A | intron_variant | Intron 1 of 2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00219 AC: 333AN: 152244Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.00170 AC: 394AN: 231904Hom.: 1 AF XY: 0.00161 AC XY: 205AN XY: 127698
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GnomAD4 exome AF: 0.00265 AC: 3857AN: 1453478Hom.: 8 Cov.: 32 AF XY: 0.00251 AC XY: 1816AN XY: 723180
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GnomAD4 genome AF: 0.00219 AC: 333AN: 152362Hom.: 0 Cov.: 34 AF XY: 0.00204 AC XY: 152AN XY: 74502
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:13Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:5
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 19, 2023 | The NOTCH1 c.2734C>T; p.Arg912Trp variant (rs201620358) is reported in the literature in individuals with aortic valve stenosis, aortic root aneurysm, bicuspid aortic valve, or coarctation of the aorta (Kerstjens-Frederikse 2016, Ziganshin 2015). Incomplete penetrance and variable expressivity are reported for NOTCH1 (Roifman 2021). This variant is also reported in ClinVar (Variation ID: 134921). This variant is found in the general population with an overall allele frequency of 0.18% (469/263284 alleles, including one homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.402). Based on the available information, the clinical significance of this variant is uncertain. References: Kerstjens-Frederikse WS et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Genet Med. 2016 Sep;18(9):914-23. PMID: 26820064. Roifman M et al. Heterozygous NOTCH1 deletion associated with variable congenital heart defects. Clin Genet. 2021 Jun;99(6):836-841. PMID: 33630301. Ziganshin BA et al. Routine Genetic Testing for Thoracic Aortic Aneurysm and Dissection in a Clinical Setting. Ann Thorac Surg. 2015 Nov;100(5):1604-11. PMID: 26188975. - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 24, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | NOTCH1: PP2, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 29, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not specified Uncertain:1Benign:2Other:1
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
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 | Apr 04, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2017 | The R912W variant of uncertain significance in the NOTCH1 gene has previously been reported in a 52 year-old male with an aortic root aneurysm and bicuspid aortic valve (Ziganshin et al., 2015). This variant has also been reported in 5 unrelated Dutch individuals with left-sided congenital heart defects; one individual with a bicuspid aortic valve, one individual with aortic valve stenosis, and three individuals with coarctation of the aorta (Kerstjens-Frederikse et al., 2016). For one of the individuals with coarctation of the aorta, this variant was also found in the father who had a bicuspid aortic valve; segregation studies for the remaining four individuals were either not completed or non-informative (Kerstjens-Frederikse et al., 2016). R912W was observed in approximately 0.3% of alleles from individuals of European (Non-Finnish) ancestry and 0.2% of alleles from individuals of both Latino and European (Finnish) ancestry in the Exome Aggregation Consortium, indicating it may be a rare benign variant in these populations (Lek et al., 2016). Furthermore, this substitution occurs at a position that is not conserved across species. Nevertheless, R912W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Likely benign, no assertion criteria provided | clinical testing | Blueprint Genetics | Jan 29, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2019 | 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. - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 27, 2020 | - - |
Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | NOTCH1 NM_017617.5 exon 17 p.Arg912Trp (c.2734C>T): This variant has been reported in the literature in one individual with an aortic aneurysm and in five individuals with nonsyndromic congenital heart disease (bicuspid aortic valve, coarctation of the aorta, aortic valve stenosis) (Ziganshin 2015 PMID:26188975, Kerstijens-Frederikse 2016 PMID:26820064). However, this variant is also present in 0.2% (317/119414) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/9-139405111-G-A). This variant is present in ClinVar (Variation ID:134921). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Aortic valve disease 1 Benign:1
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2025 | - - |
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
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