rs1554727837

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_017617.5(NOTCH1):​c.4829C>T​(p.Ala1610Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.46
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 Uncertain_significance. Variant got 3 ACMG points.

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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.4829C>T p.Ala1610Val missense_variant 26/34 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkuse as main transcriptc.4106C>T p.Ala1369Val missense_variant 23/31 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkuse as main transcriptc.4829C>T p.Ala1610Val missense_variant 26/34 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.99e-7
AC:
1
AN:
1430644
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
708668
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.12e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Adams-Oliver syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 29, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 1610 of the NOTCH1 protein (p.Ala1610Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.00070
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.61
D
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.24
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.48
T
M_CAP
Pathogenic
0.48
D
MetaRNN
Uncertain
0.69
D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
1.9
L
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.4
N
REVEL
Uncertain
0.43
Sift
Benign
0.081
T
Sift4G
Benign
0.14
T
Polyphen
0.32
B
Vest4
0.41
MutPred
0.64
Gain of MoRF binding (P = 0.1094);
MVP
0.90
MPC
1.0
ClinPred
0.67
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.21

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1554727837; hg19: chr9-139399314; API