rs775438678
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_017617.5(NOTCH1):c.3569A>G(p.His1190Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,610,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1190Q) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.3569A>G | p.His1190Arg | missense_variant | 22/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.2846A>G | p.His949Arg | missense_variant | 19/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.3569A>G | p.His1190Arg | missense_variant | 22/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151638Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000823 AC: 2AN: 242916Hom.: 0 AF XY: 0.00000752 AC XY: 1AN XY: 132910
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1459128Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 725822
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151638Hom.: 0 Cov.: 34 AF XY: 0.0000270 AC XY: 2AN XY: 74048
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | NOTCH1: PM2, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function - |
Adams-Oliver syndrome 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 21, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 575237). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1190 of the NOTCH1 protein (p.His1190Arg). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2023 | The c.3569A>G (p.H1190R) alteration is located in exon 22 (coding exon 22) of the NOTCH1 gene. This alteration results from a A to G substitution at nucleotide position 3569, causing the histidine (H) at amino acid position 1190 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 24, 2021 | - - |
Aortic valve disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at