9-136508926-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017617.5(NOTCH1):c.3115G>A(p.Gly1039Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000476 in 1,549,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.20

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

NOTCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010801673).

BP6

Variant 9-136508926-C-T is Benign according to our data. Variant chr9-136508926-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 264180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000597 (91/152364) while in subpopulation NFE AF = 0.000456 (31/68034). AF 95% confidence interval is 0.000329. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.3115G>A	p.Gly1039Ser	missense_variant	Exon 19 of 34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.2392G>A	p.Gly798Ser	missense_variant	Exon 16 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.3115G>A	p.Gly1039Ser	missense_variant	Exon 19 of 34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00489

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000829

AC:

128

AN:

154310

AF XY:

0.000693

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000471

Gnomad EAS exome

AF:

0.000182

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.000603

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000462

AC:

646

AN:

1397090

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

311

AN XY:

689172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31594

American (AMR)

AF:

0.000224

AC:

AN:

35794

Ashkenazi Jewish (ASJ)

AF:

0.000516

AC:

AN:

25172

East Asian (EAS)

AF:

0.0000558

AC:

AN:

35820

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79188

European-Finnish (FIN)

AF:

0.00491

AC:

236

AN:

48044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4378

European-Non Finnish (NFE)

AF:

0.000336

AC:

363

AN:

1079228

Other (OTH)

AF:

0.000397

AC:

AN:

57872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

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:

0.000597

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41590

American (AMR)

AF:

0.000327

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00489

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000472

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000244

AC:

ESP6500EA

AF:

0.000365

AC:

ExAC

AF:

0.000251

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NOTCH1 c.3115G>A (p.Gly1039Ser) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of 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 0.00083 in 154310 control chromosomes (gnomAD). The observed variant frequency is approximately 1300 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3115G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

Adams-Oliver syndrome 5

Benign:2

Jan 29, 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

- -

NOTCH1-related disorder

Benign:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Oct 13, 2017

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:1

Feb 02, 2021

GeneDx

Significance:Likely 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

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.76

MetaRNN

Benign

0.011

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

1.6

PhyloP100

4.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.22

REVEL

Uncertain

0.37

Sift

Benign

0.65

Sift4G

Benign

0.94

Polyphen

0.0040

Vest4

0.23

MVP

0.70

MPC

0.38

ClinPred

0.0088

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.067

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over