rs200562991
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP2PP3BP6BS2
The NM_017617.5(NOTCH1):c.1295C>T(p.Thr432Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,612,216 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00014 ( 2 hom. )
Consequence
NOTCH1
NM_017617.5 missense
NM_017617.5 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 7.85
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 -1 ACMG points.
PM1
In a binding_site (size 0) in uniprot entity NOTC1_HUMAN
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.832
BP6
Variant 9-136517898-G-A is Benign according to our data. Variant chr9-136517898-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520096.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=4, Likely_benign=1}.
BS2
High AC in GnomAd4 at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.1295C>T | p.Thr432Met | missense_variant | 8/34 | ENST00000651671.1 | NP_060087.3 | |
LOC124902310 | XR_007061865.1 | n.508-5420G>A | intron_variant, non_coding_transcript_variant | |||||
NOTCH1 | XM_011518717.3 | c.572C>T | p.Thr191Met | missense_variant | 5/31 | XP_011517019.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.1295C>T | p.Thr432Met | missense_variant | 8/34 | NM_017617.5 | ENSP00000498587 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152072Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000202 AC: 50AN: 247362Hom.: 0 AF XY: 0.000178 AC XY: 24AN XY: 134894
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GnomAD4 exome AF: 0.000140 AC: 204AN: 1460026Hom.: 2 Cov.: 35 AF XY: 0.000129 AC XY: 94AN XY: 726352
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152190Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9AN XY: 74398
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 07, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2023 | The p.T432M variant (also known as c.1295C>T), located in coding exon 8 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 1295. The threonine at codon 432 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | NOTCH1: BS1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2024 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2024 | Variant summary: NOTCH1 c.1295C>T (p.Thr432Met) results in a non-conservative amino acid change located in an EGF-like calcium-binding repeat domain (IPR049883) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 1605242 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 215-fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). To our knowledge, no occurrence of c.1295C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 520096). Based on the evidence outlined above, the variant was classified as benign. - |
NOTCH1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 09, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 27, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
Splicing
Name
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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