rs41309764
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017617.5(NOTCH1):c.3319C>T(p.Arg1107*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017617.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 39
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23798201, 34065301, 31654484, 35947102, 16025100) -
Aortic valve disease 1 Pathogenic:1
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Adams-Oliver syndrome 5 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg1107*) in the NOTCH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NOTCH1 are known to be pathogenic (PMID: 16025100, 21457232, 25132448, 25963545). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with NOTCH1-related conditions (PMID: 16025100, 23798201, 31654484). It has also been observed to segregate with disease in related individuals. This variant is also known as R1108X. ClinVar contains an entry for this variant (Variation ID: 12476). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at