9-136517826-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_017617.5(NOTCH1):​c.1367G>A​(p.Cys456Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C456C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Consequence

NOTCH1
NM_017617.5 missense

Scores

17
1
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.67
Variant links:
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 Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 5 uncertain in NM_017617.5
PM2
Very rare variant in population databases, with high coverage;
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, 0.997
PP5
Variant 9-136517826-C-T is Pathogenic according to our data. Variant chr9-136517826-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219377.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.1367G>A p.Cys456Tyr missense_variant 8/34 ENST00000651671.1
LOC124902310XR_007061865.1 linkuse as main transcriptn.508-5492C>T intron_variant, non_coding_transcript_variant
NOTCH1XM_011518717.3 linkuse as main transcriptc.644G>A p.Cys215Tyr missense_variant 5/31

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOTCH1ENST00000651671.1 linkuse as main transcriptc.1367G>A p.Cys456Tyr missense_variant 8/34 NM_017617.5 P1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Adams-Oliver syndrome 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchMolecular and Medical Genetics Group, King's College LondonFeb 24, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
4.7
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-9.7
D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
1.0
MutPred
0.99
Gain of phosphorylation at C456 (P = 0.0731);
MVP
0.98
MPC
1.6
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs864622058; hg19: chr9-139412278; COSMIC: COSV53046494; COSMIC: COSV53046494; API