chr9-136508288-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_017617.5(NOTCH1):c.3269C>G(p.Thr1090Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,816 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. T1090A) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.3269C>G | p.Thr1090Ser | missense_variant | 20/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.2546C>G | p.Thr849Ser | missense_variant | 17/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.3269C>G | p.Thr1090Ser | missense_variant | 20/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000806 AC: 2AN: 248010Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135008
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1460596Hom.: 0 Cov.: 38 AF XY: 0.0000220 AC XY: 16AN XY: 726632
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74358
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2022 | Reported in a patient with bicuspid aortic valve in the published literature (Kent et al., 2013); 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: 30371227, 23102684) - |
Adams-Oliver syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1090 of the NOTCH1 protein (p.Thr1090Ser). This variant is present in population databases (rs761508282, gnomAD 0.002%). This missense change has been observed in individual(s) with aortic valve calcification and severe calcification and dysfunction of tricuspid aortic valve (PMID: 23102684). ClinVar contains an entry for this variant (Variation ID: 544171). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOTCH1 protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at