rs201163739
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2
The NM_017617.5(NOTCH1):c.3011C>T(p.Ser1004Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,563,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S1004A) has been classified as Uncertain significance.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.3011C>T | p.Ser1004Leu | missense_variant | 19/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.2288C>T | p.Ser763Leu | missense_variant | 16/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.3011C>T | p.Ser1004Leu | missense_variant | 19/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152260Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.000173 AC: 30AN: 173498Hom.: 0 AF XY: 0.000150 AC XY: 14AN XY: 93168
GnomAD4 exome AF: 0.000112 AC: 158AN: 1411060Hom.: 0 Cov.: 35 AF XY: 0.000110 AC XY: 77AN XY: 697274
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152260Hom.: 0 Cov.: 35 AF XY: 0.000134 AC XY: 10AN XY: 74384
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2023 | Has not been published in association with cardiovascular disease; 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: 27870570) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 23, 2022 | PP2 - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2022 | The p.S1004L variant (also known as c.3011C>T), located in coding exon 19 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 3011. The serine at codon 1004 is replaced by leucine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 25, 2018 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 14, 2023 | Variant summary: NOTCH1 c.3011C>T (p.Ser1004Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR008297) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 173498 control chromosomes. The observed variant frequency is approximately 280 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3011C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=3) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
NOTCH1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 28, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | - - |
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Jun 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at