rs200871631
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_017617.5(NOTCH1):c.3374C>T(p.Ala1125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,609,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict 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. A1125T) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.3374C>T | p.Ala1125Val | missense_variant | 21/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.2651C>T | p.Ala884Val | missense_variant | 18/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.3374C>T | p.Ala1125Val | missense_variant | 21/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152208Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000941 AC: 23AN: 244358Hom.: 0 AF XY: 0.0000973 AC XY: 13AN XY: 133630
GnomAD4 exome AF: 0.0000563 AC: 82AN: 1457122Hom.: 0 Cov.: 32 AF XY: 0.0000648 AC XY: 47AN XY: 725092
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152326Hom.: 0 Cov.: 34 AF XY: 0.0000805 AC XY: 6AN XY: 74492
ClinVar
Submissions by phenotype
Adams-Oliver syndrome 5 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2020 | Has not been previously published in association with connective tissue disorders as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 409037; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29200162) - |
Aortic valve disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
NOTCH1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 16, 2023 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at