rs61751489

Positions:

chr9-136496886-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_017617.5(NOTCH1):c.6853G>A(p.Val2285Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,612,814 control chromosomes in the GnomAD database, including 902 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 83 hom., cov: 33)

Exomes 𝑓: 0.019 ( 819 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13O:1

Conservation

PhyloP100: 0.506

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016611814).

BP6

Variant 9-136496886-C-T is Benign according to our data. Variant chr9-136496886-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136496886-C-T is described in Lovd as [Benign]. Variant chr9-136496886-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5 linkuse as main transcript	c.6853G>A	p.Val2285Ile	missense_variant	34/34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3 linkuse as main transcript	c.6130G>A	p.Val2044Ile	missense_variant	31/31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.6853G>A	p.Val2285Ile	missense_variant	34/34		NM_017617.5	ENSP00000498587	P1

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2832

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00528

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0933

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0312

AC:

7684

AN:

246434

Hom.:

509

AF XY:

0.0254

AC XY:

3423

AN XY:

134818

show subpopulations

Gnomad AFR exome

AF:

0.00513

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.00433

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00559

Gnomad FIN exome

AF:

0.00659

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0188

AC:

27529

AN:

1460488

Hom.:

819

Cov.:

AF XY:

0.0180

AC XY:

13058

AN XY:

726554

show subpopulations

Gnomad4 AFR exome

AF:

0.00394

Gnomad4 AMR exome

AF:

0.153

Gnomad4 ASJ exome

AF:

0.00444

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00536

Gnomad4 FIN exome

AF:

0.00721

Gnomad4 NFE exome

AF:

0.0167

Gnomad4 OTH exome

AF:

0.0173

GnomAD4 genome

AF:

0.0187

AC:

2841

AN:

152326

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1411

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00527

Gnomad4 AMR

AF:

0.0938

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00499

Gnomad4 NFE

AF:

0.0155

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0260

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.00489

AC:

ESP6500EA

AF:

0.0162

AC:

135

ExAC

AF:

0.0247

AC:

2983

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0145

EpiControl

AF:

0.0142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Adams-Oliver syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Hypoplastic left heart syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2015

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.0

DANN

Benign

0.70

DEOGEN2

Benign

0.30

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.11

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.070

REVEL

Benign

0.079

Sift

Benign

0.52

Sift4G

Benign

0.62

Polyphen

0.0040

Vest4

0.025

MPC

0.29

ClinPred

0.0013

GERP RS

2.7

Varity_R

0.025

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over