rs200881673
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6BS2_Supporting
The NM_000435.3(NOTCH3):c.351C>T(p.Cys117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000237 in 1,603,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
NOTCH3
NM_000435.3 synonymous
NM_000435.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.25
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 Likely_benign. Variant got -2 ACMG points.
BP6
?
Variant 19-15192288-G-A is Benign according to our data. Variant chr19-15192288-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 789517.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS2
?
High AC in GnomAd4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH3 | NM_000435.3 | c.351C>T | p.Cys117= | synonymous_variant | 4/33 | ENST00000263388.7 | |
NOTCH3 | XM_005259924.5 | c.351C>T | p.Cys117= | synonymous_variant | 4/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.351C>T | p.Cys117= | synonymous_variant | 4/33 | 1 | NM_000435.3 | P1 | |
NOTCH3 | ENST00000601011.1 | c.348C>T | p.Cys116= | synonymous_variant | 4/23 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000177 AC: 4AN: 226602Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 123396
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GnomAD4 exome AF: 0.0000207 AC: 30AN: 1451068Hom.: 0 Cov.: 40 AF XY: 0.0000208 AC XY: 15AN XY: 721104
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74434
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 14, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Uncertain:1
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
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
DS_AG_spliceai
Position offset: -11
Find out detailed SpliceAI scores and Pangolin per-transcript scores at