9-136496133-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017617.5(NOTCH1):c.7606G>A(p.Val2536Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,609,464 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V2536V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.72

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04889512).

BP6

Variant 9-136496133-C-T is Benign according to our data. Variant chr9-136496133-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477975.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000578 (88/152212) while in subpopulation AFR AF = 0.00125 (52/41538). AF 95% confidence interval is 0.000981. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.7606G>A	p.Val2536Ile	missense_variant	Exon 34 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3 link	c.6883G>A	p.Val2295Ile	missense_variant	Exon 31 of 31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.7606G>A	p.Val2536Ile	missense_variant	Exon 34 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000364

AC:

AN:

238910

AF XY:

0.000354

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.000266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000481

Gnomad OTH exome

AF:

0.000350

GnomAD4 exome

AF:

0.000243

AC:

354

AN:

1457252

Hom.:

Cov.:

AF XY:

0.000247

AC XY:

179

AN XY:

724592

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

33472

American (AMR)

AF:

0.000270

AC:

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.0000387

AC:

AN:

25844

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39612

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51316

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000238

AC:

265

AN:

1111370

Other (OTH)

AF:

0.000448

AC:

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000578

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41538

American (AMR)

AF:

0.000393

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000570

Hom.:

Bravo

AF:

0.000631

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000502

AC:

ESP6500EA

AF:

0.000361

AC:

ExAC

AF:

0.000334

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOTCH1: BP4, BS1, BS2 -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1Benign:1

Feb 10, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2018

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 specified

Benign:2

Mar 16, 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. -

Jun 17, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NOTCH1-related disorder

Benign:1

Jan 28, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Adams-Oliver syndrome 5

Benign:1

Dec 26, 2024

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

0.053

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.18

CADD

Benign

7.4

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.15

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.81

M_CAP

Benign

0.021

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.1

PhyloP100

1.7

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.070

REVEL

Uncertain

0.39

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.65

MVP

0.81

MPC

0.29

ClinPred

0.00094

GERP RS

0.94

Varity_R

0.022

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