rs559917218

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP2PP3BP4_StrongBP6BS2

The NM_017617.5(NOTCH1):​c.2495C>T​(p.Pro832Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,396 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

8
8
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: 9.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

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
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.053106725).
BP6
Variant 9-136511244-G-A is Benign according to our data. Variant chr9-136511244-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134918.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, not_provided=1}.
BS2
High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.2495C>T p.Pro832Leu missense_variant 16/34 ENST00000651671.1 NP_060087.3
LOC124902310XR_007061865.1 linkuse as main transcriptn.507+1265G>A intron_variant, non_coding_transcript_variant
NOTCH1XM_011518717.3 linkuse as main transcriptc.1772C>T p.Pro591Leu missense_variant 13/31 XP_011517019.2
LOC124902310XR_007061864.1 linkuse as main transcriptn.722G>A non_coding_transcript_exon_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkuse as main transcriptc.2495C>T p.Pro832Leu missense_variant 16/34 NM_017617.5 ENSP00000498587 P1

Frequencies

GnomAD3 genomes
AF:
0.000368
AC:
56
AN:
152138
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00308
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000536
AC:
132
AN:
246062
Hom.:
0
AF XY:
0.000417
AC XY:
56
AN XY:
134434
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00372
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000180
Gnomad OTH exome
AF:
0.000335
GnomAD4 exome
AF:
0.000149
AC:
218
AN:
1460140
Hom.:
0
Cov.:
33
AF XY:
0.000139
AC XY:
101
AN XY:
726374
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00427
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000368
AC:
56
AN:
152256
Hom.:
1
Cov.:
33
AF XY:
0.000511
AC XY:
38
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00307
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000155
Hom.:
0
Bravo
AF:
0.000548
ExAC
AF:
0.000364
AC:
44
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:1Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 21, 2023- -
Aortic valve disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNew York Genome CenterMay 31, 2019- -
NOTCH1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 09, 2019This 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). -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 01, 2018This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 16, 2020- -
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.82
D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.62
D
MetaRNN
Benign
0.053
T
MetaSVM
Uncertain
0.59
D
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.9
D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.79
MVP
0.78
MPC
1.2
ClinPred
0.19
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs559917218; hg19: chr9-139405696; API