rs773847667
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_017617.5(NOTCH1):c.2806G>C(p.Gly936Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. G936S) 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_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.2806G>C | p.Gly936Arg | missense_variant | 18/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.424C>G | non_coding_transcript_exon_variant | 1/3 | |||
NOTCH1 | XM_011518717.3 | c.2083G>C | p.Gly695Arg | missense_variant | 15/31 | ||
LOC124902310 | XR_007061864.1 | n.424C>G | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.2806G>C | p.Gly936Arg | missense_variant | 18/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Adams-Oliver syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 936 of the NOTCH1 protein (p.Gly936Arg). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.