rs61751557

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017617.5(NOTCH1):​c.711C>T​(p.Gly237Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,524,882 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 97 hom., cov: 34)
Exomes 𝑓: 0.0020 ( 65 hom. )

Consequence

NOTCH1
NM_017617.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.50

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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 9-136522881-G-A is Benign according to our data. Variant chr9-136522881-G-A is described in CliVar as Benign. Clinvar id is 197310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136522881-G-A is described in CliVar as Benign. Clinvar id is 197310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136522881-G-A is described in CliVar as Benign. Clinvar id is 197310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136522881-G-A is described in CliVar as Benign. Clinvar id is 197310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136522881-G-A is described in CliVar as Benign. Clinvar id is 197310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136522881-G-A is described in CliVar as Benign. Clinvar id is 197310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-2.5 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH1NM_017617.5 linkc.711C>T p.Gly237Gly synonymous_variant Exon 4 of 34 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkc.20-3316C>T intron_variant Intron 1 of 30 XP_011517019.2
LOC124902310XR_007061865.1 linkn.508-437G>A intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkc.711C>T p.Gly237Gly synonymous_variant Exon 4 of 34 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
AF:
0.0172
AC:
2618
AN:
152248
Hom.:
97
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0594
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00713
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000620
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.00908
GnomAD2 exomes
AF:
0.00529
AC:
718
AN:
135800
AF XY:
0.00424
show subpopulations
Gnomad AFR exome
AF:
0.0630
Gnomad AMR exome
AF:
0.00899
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000290
Gnomad OTH exome
AF:
0.00302
GnomAD4 exome
AF:
0.00202
AC:
2778
AN:
1372516
Hom.:
65
Cov.:
31
AF XY:
0.00179
AC XY:
1208
AN XY:
673826
show subpopulations
African (AFR)
AF:
0.0637
AC:
1991
AN:
31248
American (AMR)
AF:
0.00838
AC:
296
AN:
35312
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23956
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35598
South Asian (SAS)
AF:
0.000469
AC:
36
AN:
76810
European-Finnish (FIN)
AF:
0.0000241
AC:
1
AN:
41574
Middle Eastern (MID)
AF:
0.00474
AC:
21
AN:
4434
European-Non Finnish (NFE)
AF:
0.000192
AC:
205
AN:
1066750
Other (OTH)
AF:
0.00401
AC:
228
AN:
56834
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
153
306
458
611
764
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
70
140
210
280
350
<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:
0.0172
AC:
2621
AN:
152366
Hom.:
97
Cov.:
34
AF XY:
0.0166
AC XY:
1234
AN XY:
74514
show subpopulations
African (AFR)
AF:
0.0593
AC:
2464
AN:
41586
American (AMR)
AF:
0.00712
AC:
109
AN:
15314
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000621
AC:
3
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.0102
AC:
3
AN:
294
European-Non Finnish (NFE)
AF:
0.000338
AC:
23
AN:
68026
Other (OTH)
AF:
0.00899
AC:
19
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
117
235
352
470
587
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
28
56
84
112
140
<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:
0.00820
Hom.:
4
Bravo
AF:
0.0197
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Jan 20, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

Oct 14, 2016
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. -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Nov 13, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Adams-Oliver syndrome 5 Benign:2
Feb 03, 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
Apr 16, 2015
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as 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;C4014970:Adams-Oliver syndrome 5 Benign:1
Jul 13, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
-0.63
CADD
Benign
1.5
DANN
Benign
0.80
PhyloP100
-2.5
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs61751557; hg19: chr9-139417333; COSMIC: COSV53037665; COSMIC: COSV53037665; API