rs1348892740
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017617.5(NOTCH1):c.166C>T(p.Arg56Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,411,294 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R56R) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.166C>T | p.Arg56Ter | stop_gained | 3/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.623+521G>A | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.20-4389C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.166C>T | p.Arg56Ter | stop_gained | 3/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.00000622 AC: 1AN: 160644Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 87106
GnomAD4 exome AF: 7.09e-7 AC: 1AN: 1411294Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 697798
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2022 | Reported as a de novo variant in a proband referred for exome sequencing; however, detailed clinical information was not provided (Powis et al., 2018); 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: 29565416) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | NOTCH1: PVS1, PM2 - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at