chr9-136513527-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP2PP3BP6

The NM_017617.5(NOTCH1):​c.2218G>T​(p.Asp740Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D740N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

2
6
11

Clinical Significance

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

Conservation

PhyloP100: 0.763
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.795
BP6
Variant 9-136513527-C-A is Benign according to our data. Variant chr9-136513527-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1787871.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.2218G>T p.Asp740Tyr missense_variant 14/34 ENST00000651671.1
LOC124902310XR_007061865.1 linkuse as main transcriptn.507+3548C>A intron_variant, non_coding_transcript_variant
NOTCH1XM_011518717.3 linkuse as main transcriptc.1495G>T p.Asp499Tyr missense_variant 11/31

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOTCH1ENST00000651671.1 linkuse as main transcriptc.2218G>T p.Asp740Tyr missense_variant 14/34 NM_017617.5 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247828
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
135032
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460698
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
726638
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 09, 2022The p.D740Y variant (also known as c.2218G>T), located in coding exon 14 of the NOTCH1 gene, results from a G to T substitution at nucleotide position 2218. The aspartic acid at codon 740 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJun 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
13
DANN
Benign
0.96
DEOGEN2
Uncertain
0.43
T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.30
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.79
D
MetaSVM
Uncertain
-0.094
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
0.99
D
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.2
N
REVEL
Pathogenic
0.65
Sift
Benign
1.0
T
Sift4G
Benign
0.17
T
Polyphen
0.60
P
Vest4
0.76
MutPred
0.64
Loss of disorder (P = 0.0351);
MVP
0.93
MPC
0.90
ClinPred
0.43
T
GERP RS
2.9
Varity_R
0.093

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: rs200816814; hg19: chr9-139407979; API