rs114207045
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP3BP6_Very_StrongBS1BS2
The NM_000435.3(NOTCH3):c.1490C>T(p.Ser497Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00527 in 1,593,160 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S497W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000435.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH3 | NM_000435.3 | c.1490C>T | p.Ser497Leu | missense_variant, splice_region_variant | 9/33 | ENST00000263388.7 | |
NOTCH3 | XM_005259924.5 | c.1490C>T | p.Ser497Leu | missense_variant, splice_region_variant | 9/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.1490C>T | p.Ser497Leu | missense_variant, splice_region_variant | 9/33 | 1 | NM_000435.3 | P1 | |
NOTCH3 | ENST00000601011.1 | c.1487C>T | p.Ser496Leu | missense_variant, splice_region_variant | 9/23 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00747 AC: 1136AN: 152062Hom.: 6 Cov.: 32
GnomAD3 exomes AF: 0.00669 AC: 1490AN: 222722Hom.: 12 AF XY: 0.00670 AC XY: 805AN XY: 120082
GnomAD4 exome AF: 0.00504 AC: 7256AN: 1440980Hom.: 37 Cov.: 31 AF XY: 0.00515 AC XY: 3682AN XY: 714970
GnomAD4 genome ? AF: 0.00746 AC: 1136AN: 152180Hom.: 6 Cov.: 32 AF XY: 0.00785 AC XY: 584AN XY: 74398
ClinVar
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | NOTCH3: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 12, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at