rs61751535

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_017617.5(NOTCH1):​c.5445C>T​(p.Asp1815Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,613,164 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

NOTCH1
NM_017617.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.08

Publications

3 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 -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 9-136502028-G-A is Benign according to our data. Variant chr9-136502028-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 477946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136502028-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 477946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136502028-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 477946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136502028-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 477946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136502028-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 477946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136502028-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 477946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136502028-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 477946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.08 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00282 (429/152184) while in subpopulation AFR AF = 0.00942 (391/41522). AF 95% confidence interval is 0.00865. There are 1 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High AC in GnomAd4 at 429 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH1NM_017617.5 linkc.5445C>T p.Asp1815Asp synonymous_variant Exon 29 of 34 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkc.4722C>T p.Asp1574Asp synonymous_variant Exon 26 of 31 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkc.5445C>T p.Asp1815Asp synonymous_variant Exon 29 of 34 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
AF:
0.00276
AC:
420
AN:
152066
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00923
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00198
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00143
GnomAD2 exomes
AF:
0.000796
AC:
198
AN:
248618
AF XY:
0.000621
show subpopulations
Gnomad AFR exome
AF:
0.0107
Gnomad AMR exome
AF:
0.000608
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000512
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000286
AC:
418
AN:
1460980
Hom.:
1
Cov.:
35
AF XY:
0.000245
AC XY:
178
AN XY:
726804
show subpopulations
African (AFR)
AF:
0.00935
AC:
313
AN:
33478
American (AMR)
AF:
0.000783
AC:
35
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.0000464
AC:
4
AN:
86258
European-Finnish (FIN)
AF:
0.000380
AC:
20
AN:
52596
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000989
AC:
11
AN:
1111956
Other (OTH)
AF:
0.000563
AC:
34
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
33
66
98
131
164
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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:
0.00282
AC:
429
AN:
152184
Hom.:
1
Cov.:
33
AF XY:
0.00278
AC XY:
207
AN XY:
74404
show subpopulations
African (AFR)
AF:
0.00942
AC:
391
AN:
41522
American (AMR)
AF:
0.000654
AC:
10
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5166
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00198
AC:
21
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
67986
Other (OTH)
AF:
0.00142
AC:
3
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
21
42
64
85
106
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00147
Hom.:
1
Bravo
AF:
0.00314
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Jul 21, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 18, 2017
GeneDx
Significance: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. -

Adams-Oliver syndrome 5 Benign:2
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 15, 2022
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1
Mar 17, 2016
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. -

Aortic valve disease 1 Benign:1
Mar 15, 2022
Genome-Nilou Lab
Significance: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
-0.46
CADD
Benign
4.8
DANN
Benign
0.91
PhyloP100
-1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=96/4
polymorphism

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: rs61751535; hg19: chr9-139396480; COSMIC: COSV53065153; COSMIC: COSV53065153; API