rs954507677
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BP6
The NM_017617.5(NOTCH1):c.4271T>C(p.Leu1424Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. L1424L) 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 -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.4271T>C | p.Leu1424Ser | missense_variant | 25/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.3548T>C | p.Leu1183Ser | missense_variant | 22/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.4271T>C | p.Leu1424Ser | missense_variant | 25/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245798Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134282
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1459864Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 726192
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2024 | The p.L1424S variant (also known as c.4271T>C), located in coding exon 25 of the NOTCH1 gene, results from a T to C substitution at nucleotide position 4271. The leucine at codon 1424 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2023 | - - |
Aortic valve disorder;C4014970:Adams-Oliver syndrome 5 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 01-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at