rs202235419
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP6_ModerateBS2
The NM_017617.5(NOTCH1):c.1077C>T(p.Cys359=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000254 in 1,612,710 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 Benign (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
NOTCH1
NM_017617.5 synonymous
NM_017617.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 4.45
Genes affected
NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
Variant 9-136518613-G-A is Benign according to our data. Variant chr9-136518613-G-A is described in ClinVar as [Benign]. Clinvar id is 241115.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.1077C>T | p.Cys359= | synonymous_variant | 6/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.508-4705G>A | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.354C>T | p.Cys118= | synonymous_variant | 3/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.1077C>T | p.Cys359= | synonymous_variant | 6/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000202 AC: 5AN: 246920Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134522
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GnomAD4 exome AF: 0.0000247 AC: 36AN: 1460398Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18AN XY: 726516
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74486
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NOTCH1 p.Cys359Cys variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs202235419) and ClinVar (classified as a variant of uncertain significance by Invitae for Adams-Oliver syndrome 5). The variant was identified in control databases in 5 of 246920 chromosomes at a frequency of 0.00002025 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 3 of 18082 chromosomes (freq: 0.000166), South Asian in 1 of 30592 chromosomes (freq: 0.000033) and Latino in 1 of 34456 chromosomes (freq: 0.000029), but was not observed in the African, Ashkenazi Jewish, European (Finnish), European (non-Finnish), or Other populations. The p.Cys359Cys variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, however 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this has not been confirmed through RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Adams-Oliver syndrome 5 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2022 | - - |
Computational scores
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Name
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BayesDel_noAF
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DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at