rs1356199208
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_017617.5(NOTCH1):c.5284C>T(p.Arg1762Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1762Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.5284C>T | p.Arg1762Trp | missense_variant | 28/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.4561C>T | p.Arg1521Trp | missense_variant | 25/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.5284C>T | p.Arg1762Trp | missense_variant | 28/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000828 AC: 2AN: 241630Hom.: 0 AF XY: 0.00000753 AC XY: 1AN XY: 132822
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460008Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726320
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Adams-Oliver syndrome 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2017 | This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NOTCH1-related disease. This sequence change replaces arginine with tryptophan at codon 1762 of the NOTCH1 protein (p.Arg1762Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2023 | Has not been previously published in association with cardiac or connective tissue disease to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24277457) - |
Aortic valve disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at