9-136515599-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2
The NM_017617.5(NOTCH1):c.1787C>T(p.Thr596Met) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,609,616 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic 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. T596T) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.1787C>T | p.Thr596Met | missense_variant | 11/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.507+5620G>A | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.1064C>T | p.Thr355Met | missense_variant | 8/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.1787C>T | p.Thr596Met | missense_variant | 11/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000149 AC: 36AN: 240946Hom.: 2 AF XY: 0.0000986 AC XY: 13AN XY: 131824
GnomAD4 exome AF: 0.000167 AC: 244AN: 1457306Hom.: 2 Cov.: 34 AF XY: 0.000153 AC XY: 111AN XY: 725042
GnomAD4 genome AF: 0.000197 AC: 30AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74496
ClinVar
Submissions by phenotype
Aortic valve disease 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 14, 2006 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2022 | The p.T596M variant (also known as c.1787C>T), located in coding exon 11 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 1787. The threonine at codon 596 is replaced by methionine, an amino acid with similar properties. This variant (also referred to as c.1963 C>T) was reported in a patient with bicuspid aortic valve (Mohamed SA et al, Biochem. Biophys. Res. Commun. 2006 Jul; 345(4):1460-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2021 | This variant is associated with the following publications: (PMID: 17662764, 16729972) - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | - - |
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at