9-136502432-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_017617.5(NOTCH1):c.5224G>A(p.Ala1742Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1742S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NOTCH1
NM_017617.5 missense
NM_017617.5 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 5.88
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, NOTCH1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.5224G>A | p.Ala1742Thr | missense_variant | 28/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.4501G>A | p.Ala1501Thr | missense_variant | 25/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.5224G>A | p.Ala1742Thr | missense_variant | 28/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1456064Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 724188
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1456064
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
724188
Gnomad4 AFR exome
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Gnomad4 AMR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 NFE exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2024 | The c.5224G>A (p.A1742T) alteration is located in exon 28 (coding exon 28) of the NOTCH1 gene. This alteration results from a G to A substitution at nucleotide position 5224, causing the alanine (A) at amino acid position 1742 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of helix (P = 0.0093);
MVP
MPC
ClinPred
D
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