rs375025242

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017617.5(NOTCH1):​c.7400C>T​(p.Ser2467Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,593,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 5.03
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 -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03067547).
BP6
Variant 9-136496339-G-A is Benign according to our data. Variant chr9-136496339-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134947.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, not_provided=1}.
BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH1NM_017617.5 linkc.7400C>T p.Ser2467Leu missense_variant Exon 34 of 34 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkc.6677C>T p.Ser2226Leu missense_variant Exon 31 of 31 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkc.7400C>T p.Ser2467Leu missense_variant Exon 34 of 34 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000125
AC:
27
AN:
215786
Hom.:
0
AF XY:
0.000144
AC XY:
17
AN XY:
117734
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000216
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000701
Gnomad FIN exome
AF:
0.00100
Gnomad NFE exome
AF:
0.0000817
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000152
AC:
219
AN:
1440838
Hom.:
0
Cov.:
31
AF XY:
0.000148
AC XY:
106
AN XY:
714664
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000780
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000708
Gnomad4 FIN exome
AF:
0.000612
Gnomad4 NFE exome
AF:
0.000162
Gnomad4 OTH exome
AF:
0.0000502
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152198
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000941
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000716
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000119
AC:
1
ExAC
AF:
0.000125
AC:
15

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
Jan 28, 2014
Blueprint Genetics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 14, 2020
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1Other:1
Jan 28, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: NOTCH1 c.7400C>T (p.Ser2467Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 215786 control chromosomes. The observed variant frequency is approximately 200.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). To our knowledge, no occurrence of c.7400C>T in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134947). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

not provided Uncertain:1
Feb 16, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously reported in association with TAAD to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30341550, 24728327) -

Adams-Oliver syndrome 5 Benign:1
Nov 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
21
DANN
Benign
0.95
DEOGEN2
Benign
0.33
T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.67
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.84
T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.031
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.8
L
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.21
Sift
Benign
0.30
T
Sift4G
Benign
0.52
T
Polyphen
0.64
P
Vest4
0.15
MVP
0.86
MPC
0.39
ClinPred
0.050
T
GERP RS
2.6
Varity_R
0.080

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: rs375025242; hg19: chr9-139390791; API