chr9-136518596-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP2BS2
The NM_017617.5(NOTCH1):c.1094G>A(p.Arg365His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,611,678 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. R365C) has been classified as Likely pathogenic.
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.1094G>A | p.Arg365His | missense_variant | 6/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.508-4722C>T | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.371G>A | p.Arg124His | missense_variant | 3/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.1094G>A | p.Arg365His | missense_variant | 6/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244052Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133246
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1459500Hom.: 0 Cov.: 32 AF XY: 0.0000152 AC XY: 11AN XY: 726026
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
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 | Jan 25, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2020 | Has not been previously reported as pathogenic or benign in association with connective tissue disorders or congenital heart defects to our knowledge; Identified in conjunction with additional variants in individuals referred for connective tissue disorder genetic testing at GeneDx; segregation data is limited or absent at this time; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 544174; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25104330) - |
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