rs373713957
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_017617.5(NOTCH1):c.432C>T(p.Cys144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,604,098 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00038 ( 3 hom. )
Consequence
NOTCH1
NM_017617.5 synonymous
NM_017617.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.198
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 -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
?
Variant 9-136523160-G-A is Benign according to our data. Variant chr9-136523160-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136523160-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.198 with no splicing effect.
BS2
?
High AC in GnomAd4 at 51 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.432C>T | p.Cys144= | synonymous_variant | 4/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.508-158G>A | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.20-3595C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.432C>T | p.Cys144= | synonymous_variant | 4/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000335 AC: 51AN: 152228Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000484 AC: 110AN: 227308Hom.: 0 AF XY: 0.000531 AC XY: 66AN XY: 124240
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GnomAD4 exome AF: 0.000377 AC: 548AN: 1451870Hom.: 3 Cov.: 31 AF XY: 0.000403 AC XY: 291AN XY: 721444
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GnomAD4 genome ? AF: 0.000335 AC: 51AN: 152228Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23AN XY: 74368
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | NOTCH1: BP4, BP7 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2024 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 21, 2016 | 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 | Oct 23, 2018 | - - |
Adams-Oliver syndrome 5 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Aortic valve disease 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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