rs864622727
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_017617.5(NOTCH1):c.4067G>T(p.Arg1356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1356C) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NOTCH1
NM_017617.5 missense
NM_017617.5 missense
Scores
4
15
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.738
Publications
1 publications found
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]
NOTCH1 Gene-Disease associations (from GenCC):
- Adams-Oliver syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
- Adams-Oliver syndrome 5Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
- aortic valve disease 1Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
- connective tissue disorderInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- leukodystrophyInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- familial bicuspid aortic valveInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152178
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1439668Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 715766
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1439668
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
715766
African (AFR)
AF:
AC:
0
AN:
33302
American (AMR)
AF:
AC:
0
AN:
43912
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25804
East Asian (EAS)
AF:
AC:
0
AN:
39492
South Asian (SAS)
AF:
AC:
0
AN:
85550
European-Finnish (FIN)
AF:
AC:
0
AN:
38718
Middle Eastern (MID)
AF:
AC:
0
AN:
5652
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1107496
Other (OTH)
AF:
AC:
0
AN:
59742
GnomAD4 genome 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74348 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152178
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74348
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41434
American (AMR)
AF:
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5188
South Asian (SAS)
AF:
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
AC:
1
AN:
10622
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68024
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
PhyloP100
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of disorder (P = 0.0607);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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