9-136515687-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017617.5(NOTCH1):​c.1699A>G​(p.Ile567Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,552,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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: š‘“ 0.00016 ( 0 hom., cov: 33)
Exomes š‘“: 0.000096 ( 1 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 2.66
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 -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011598438).
BP6
Variant 9-136515687-T-C is Benign according to our data. Variant chr9-136515687-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134907.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1, not_provided=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000164 (25/152294) while in subpopulation EAS AF= 0.00251 (13/5178). AF 95% confidence interval is 0.00149. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH1NM_017617.5 linkc.1699A>G p.Ile567Val missense_variant Exon 11 of 34 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkc.976A>G p.Ile326Val missense_variant Exon 8 of 31 XP_011517019.2
LOC124902310XR_007061865.1 linkn.507+5708T>C intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkc.1699A>G p.Ile567Val missense_variant Exon 11 of 34 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00250
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000364
AC:
57
AN:
156768
Hom.:
0
AF XY:
0.000389
AC XY:
33
AN XY:
84750
show subpopulations
Gnomad AFR exome
AF:
0.000114
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00326
Gnomad SAS exome
AF:
0.000661
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000154
Gnomad OTH exome
AF:
0.000223
GnomAD4 exome
AF:
0.0000964
AC:
135
AN:
1400352
Hom.:
1
Cov.:
34
AF XY:
0.000127
AC XY:
88
AN XY:
692620
show subpopulations
Gnomad4 AFR exome
AF:
0.0000624
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00126
Gnomad4 SAS exome
AF:
0.000556
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000101
Gnomad4 OTH exome
AF:
0.000532
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152294
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
13
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00251
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000144
ExAC
AF:
0.000149
AC:
17
Asia WGS
AF:
0.00693
AC:
24
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:2
Feb 01, 2018
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 27, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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:2
Oct 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NOTCH1: PP2, BS1, BS2 -

Mar 27, 2018
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Nov 26, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Adams-Oliver syndrome 5 Benign:1
Jan 21, 2025
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
0.068
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
12
DANN
Uncertain
0.98
DEOGEN2
Benign
0.33
T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.80
T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.012
T
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Benign
0.55
N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.69
N
REVEL
Uncertain
0.37
Sift
Benign
0.063
T
Sift4G
Benign
0.14
T
Polyphen
0.019
B
Vest4
0.41
MVP
0.75
MPC
0.32
ClinPred
0.026
T
GERP RS
5.0
Varity_R
0.058

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: rs369067940; hg19: chr9-139410139; COSMIC: COSV53059861; COSMIC: COSV53059861; API