rs756972680
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_017617.5(NOTCH1):c.3853G>T(p.Val1285Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000234 in 1,455,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1285M) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.3853G>T | p.Val1285Leu | missense_variant | 23/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.3130G>T | p.Val1044Leu | missense_variant | 20/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.3853G>T | p.Val1285Leu | missense_variant | 23/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.0000127 AC: 3AN: 236138Hom.: 0 AF XY: 0.00000776 AC XY: 1AN XY: 128840
GnomAD4 exome AF: 0.0000234 AC: 34AN: 1455396Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14AN XY: 723608
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Adams-Oliver syndrome 5 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2023 | - - |
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 | Jun 10, 2023 | The p.V1285L variant (also known as c.3853G>T), located in coding exon 23 of the NOTCH1 gene, results from a G to T substitution at nucleotide position 3853. The valine at codon 1285 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | 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 - |
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