rs35887416
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The ENST00000263388.7(NOTCH3):c.5370C>T(p.Phe1790=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,614,090 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0026 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 5 hom. )
Consequence
NOTCH3
ENST00000263388.7 synonymous
ENST00000263388.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.94
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 -18 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 19-15166084-G-A is Benign according to our data. Variant chr19-15166084-G-A is described in ClinVar as [Benign]. Clinvar id is 256142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00261 (398/152308) while in subpopulation AFR AF= 0.00893 (371/41564). AF 95% confidence interval is 0.00818. There are 1 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 398 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOTCH3 | NM_000435.3 | c.5370C>T | p.Phe1790= | synonymous_variant | 30/33 | ENST00000263388.7 | NP_000426.2 | |
NOTCH3 | XM_005259924.5 | c.5214C>T | p.Phe1738= | synonymous_variant | 29/32 | XP_005259981.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NOTCH3 | ENST00000263388.7 | c.5370C>T | p.Phe1790= | synonymous_variant | 30/33 | 1 | NM_000435.3 | ENSP00000263388 | P1 | |
NOTCH3 | ENST00000595514.1 | c.229-569C>T | intron_variant, NMD_transcript_variant | 3 | ENSP00000470661 |
Frequencies
GnomAD3 genomes AF: 0.00262 AC: 399AN: 152190Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000575 AC: 144AN: 250532Hom.: 0 AF XY: 0.000384 AC XY: 52AN XY: 135500
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GnomAD4 exome AF: 0.000267 AC: 390AN: 1461782Hom.: 5 Cov.: 34 AF XY: 0.000237 AC XY: 172AN XY: 727208
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GnomAD4 genome AF: 0.00261 AC: 398AN: 152308Hom.: 1 Cov.: 32 AF XY: 0.00254 AC XY: 189AN XY: 74470
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | NOTCH3: BS1, BS2 - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 21, 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:1
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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at