chr9-136502467-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_017617.5(NOTCH1):c.5189C>T(p.Pro1730Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,583,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1730P) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.5189C>T | p.Pro1730Leu | missense_variant | 28/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.4466C>T | p.Pro1489Leu | missense_variant | 25/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.5189C>T | p.Pro1730Leu | missense_variant | 28/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152120Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000230 AC: 45AN: 195828Hom.: 0 AF XY: 0.000228 AC XY: 25AN XY: 109468
GnomAD4 exome AF: 0.000260 AC: 372AN: 1430902Hom.: 1 Cov.: 32 AF XY: 0.000259 AC XY: 184AN XY: 709322
GnomAD4 genome AF: 0.000263 AC: 40AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74434
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | NOTCH1: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
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+ | - | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2023 | The c.5189C>T (p.P1730L) alteration is located in exon 28 (coding exon 28) of the NOTCH1 gene. This alteration results from a C to T substitution at nucleotide position 5189, causing the proline (P) at amino acid position 1730 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 05, 2018 | - - |
NOTCH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 2023 | The NOTCH1 c.5189C>T variant is predicted to result in the amino acid substitution p.Pro1730Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139396919-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at