chr9-136515734-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_017617.5(NOTCH1):​c.1670-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000752 in 1,529,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 intron

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.26

Publications

0 publications found
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]
NOTCH1 Gene-Disease associations (from GenCC):
  • Adams-Oliver syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
  • Adams-Oliver syndrome 5
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
  • aortic valve disease 1
    Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
  • connective tissue disorder
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • leukodystrophy
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • familial bicuspid aortic valve
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 9-136515734-C-T is Benign according to our data. Variant chr9-136515734-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 392778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH1NM_017617.5 linkc.1670-18G>A intron_variant Intron 10 of 33 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkc.947-18G>A intron_variant Intron 7 of 30 XP_011517019.2
LOC124902310XR_007061865.1 linkn.507+5755C>T intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkc.1670-18G>A intron_variant Intron 10 of 33 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152158
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000439
AC:
6
AN:
136670
AF XY:
0.0000408
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000814
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000562
Gnomad OTH exome
AF:
0.000242
GnomAD4 exome
AF:
0.0000733
AC:
101
AN:
1377512
Hom.:
0
Cov.:
33
AF XY:
0.0000721
AC XY:
49
AN XY:
679586
show subpopulations
African (AFR)
AF:
0.000127
AC:
4
AN:
31442
American (AMR)
AF:
0.0000842
AC:
3
AN:
35650
Ashkenazi Jewish (ASJ)
AF:
0.0000399
AC:
1
AN:
25066
East Asian (EAS)
AF:
0.0000280
AC:
1
AN:
35692
South Asian (SAS)
AF:
0.0000126
AC:
1
AN:
79070
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
34160
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4062
European-Non Finnish (NFE)
AF:
0.0000781
AC:
84
AN:
1074858
Other (OTH)
AF:
0.000122
AC:
7
AN:
57512
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
7
14
22
29
36
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152158
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74322
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41436
American (AMR)
AF:
0.0000654
AC:
1
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000162
AC:
11
AN:
68006
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.532
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000831

ClinVar

Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Adams-Oliver syndrome 5 Benign:2
Mar 15, 2022
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Jan 16, 2017
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. -

Aortic valve disease 1 Benign:1
Mar 15, 2022
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Connective tissue disorder Benign:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.0020
DANN
Benign
0.73
PhyloP100
-2.3

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

Other links and lift over

dbSNP: rs375041394; hg19: chr9-139410186; API