rs750242131
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2
The NM_017617.5(NOTCH1):c.454G>A(p.Gly152Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000859 in 1,605,648 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G152G) 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.454G>A | p.Gly152Ser | missense_variant | 4/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.508-180C>T | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.20-3573G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.454G>A | p.Gly152Ser | missense_variant | 4/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152222Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000522 AC: 12AN: 229886Hom.: 0 AF XY: 0.0000556 AC XY: 7AN XY: 125862
GnomAD4 exome AF: 0.0000798 AC: 116AN: 1453426Hom.: 0 Cov.: 31 AF XY: 0.0000651 AC XY: 47AN XY: 722352
GnomAD4 genome ? AF: 0.000145 AC: 22AN: 152222Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9AN XY: 74362
ClinVar
Submissions by phenotype
Adams-Oliver syndrome 5 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | - - |
NOTCH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 03, 2023 | The NOTCH1 c.454G>A variant is predicted to result in the amino acid substitution p.Gly152Ser. This variant has been reported in one individual with bicuspid aortic valve (BAV); however, the same study also reported that the variant was not significantly associated with BAV (Dargis et al. 2016. PubMed ID: 26708639). This variant is reported in 0.022% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139417590-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 14, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2021 | Reported in one individual with bicuspid aortic valve (Dargis et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#409074; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26708639) - |
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