rs3815188
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000435.3(NOTCH3):c.303C>T(p.Thr101=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,611,970 control chromosomes in the GnomAD database, including 22,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.18 ( 2776 hom., cov: 31)
Exomes 𝑓: 0.16 ( 20040 hom. )
Consequence
NOTCH3
NM_000435.3 synonymous
NM_000435.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0660
Genes affected
NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
?
Variant 19-15192414-G-A is Benign according to our data. Variant chr19-15192414-G-A is described in ClinVar as [Benign]. Clinvar id is 256131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15192414-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.066 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH3 | NM_000435.3 | c.303C>T | p.Thr101= | synonymous_variant | 3/33 | ENST00000263388.7 | |
NOTCH3 | XM_005259924.5 | c.303C>T | p.Thr101= | synonymous_variant | 3/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.303C>T | p.Thr101= | synonymous_variant | 3/33 | 1 | NM_000435.3 | P1 | |
NOTCH3 | ENST00000601011.1 | c.300C>T | p.Thr100= | synonymous_variant | 3/23 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.181 AC: 27482AN: 151884Hom.: 2770 Cov.: 31
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GnomAD3 exomes AF: 0.175 AC: 42778AN: 244850Hom.: 4131 AF XY: 0.169 AC XY: 22661AN XY: 133984
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GnomAD4 exome AF: 0.159 AC: 232591AN: 1459970Hom.: 20040 Cov.: 40 AF XY: 0.158 AC XY: 115115AN XY: 726318
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GnomAD4 genome ? AF: 0.181 AC: 27513AN: 152000Hom.: 2776 Cov.: 31 AF XY: 0.178 AC XY: 13246AN XY: 74302
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ClinVar
Significance: Benign
Submissions summary: Benign:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 12, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2021 | This variant is associated with the following publications: (PMID: 16949066, 31288479, 10371548, 21616505, 22153900) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 04, 2021 | - - |
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:2Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - CureCADASIL | - | Variant interpreted as Benign and reported on 06-21-2005 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Lateral meningocele syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at