rs201620358

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_017617.5(NOTCH1):c.2734C>T(p.Arg912Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,605,840 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R912Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0027 ( 8 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:13O:1

Conservation

PhyloP100: 2.57

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:

LOC124902310 (HGNC:):

LOC124902310 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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=0.105588555).

BP6

Variant 9-136510659-G-A is Benign according to our data. Variant chr9-136510659-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134921.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=4, Uncertain_significance=5, Benign=3}. Variant chr9-136510659-G-A is described in Lovd as [Likely_benign]. Variant chr9-136510659-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 333 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOTCH1	NM_017617.5 linkuse as main transcript	c.2734C>T	p.Arg912Trp	missense_variant	17/34	ENST00000651671.1
LOC124902310	XR_007061865.1 linkuse as main transcript	n.507+680G>A		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3 linkuse as main transcript	c.2011C>T	p.Arg671Trp	missense_variant	14/31
LOC124902310	XR_007061864.1 linkuse as main transcript	n.508-371G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.2734C>T	p.Arg912Trp	missense_variant	17/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00345

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00170

AC:

394

AN:

231904

Hom.:

AF XY:

0.00161

AC XY:

205

AN XY:

127698

show subpopulations

Gnomad AFR exome

AF:

0.000562

Gnomad AMR exome

AF:

0.00192

Gnomad ASJ exome

AF:

0.000513

Gnomad EAS exome

AF:

0.000172

Gnomad SAS exome

AF:

0.0000997

Gnomad FIN exome

AF:

0.00161

Gnomad NFE exome

AF:

0.00257

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00265

AC:

3857

AN:

1453478

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1816

AN XY:

723180

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00189

Gnomad4 ASJ exome

AF:

0.000691

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.00233

Gnomad4 NFE exome

AF:

0.00313

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00219

AC:

333

AN:

152362

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00345

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00293

Hom.:

Bravo

AF:

0.00215

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000495

AC:

ESP6500EA

AF:

0.00324

AC:

ExAC

AF:

0.00163

AC:

196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NOTCH1: PP2, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	The NOTCH1 c.2734C>T; p.Arg912Trp variant (rs201620358) is reported in the literature in individuals with aortic valve stenosis, aortic root aneurysm, bicuspid aortic valve, or coarctation of the aorta (Kerstjens-Frederikse 2016, Ziganshin 2015). Incomplete penetrance and variable expressivity are reported for NOTCH1 (Roifman 2021). This variant is also reported in ClinVar (Variation ID: 134921). This variant is found in the general population with an overall allele frequency of 0.18% (469/263284 alleles, including one homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.402). Based on the available information, the clinical significance of this variant is uncertain. References: Kerstjens-Frederikse WS et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Genet Med. 2016 Sep;18(9):914-23. PMID: 26820064. Roifman M et al. Heterozygous NOTCH1 deletion associated with variable congenital heart defects. Clin Genet. 2021 Jun;99(6):836-841. PMID: 33630301. Ziganshin BA et al. Routine Genetic Testing for Thoracic Aortic Aneurysm and Dissection in a Clinical Setting. Ann Thorac Surg. 2015 Nov;100(5):1604-11. PMID: 26188975. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 04, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 24, 2021	- -

not specified

Uncertain:1Benign:2Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2017	The R912W variant of uncertain significance in the NOTCH1 gene has previously been reported in a 52 year-old male with an aortic root aneurysm and bicuspid aortic valve (Ziganshin et al., 2015). This variant has also been reported in 5 unrelated Dutch individuals with left-sided congenital heart defects; one individual with a bicuspid aortic valve, one individual with aortic valve stenosis, and three individuals with coarctation of the aorta (Kerstjens-Frederikse et al., 2016). For one of the individuals with coarctation of the aorta, this variant was also found in the father who had a bicuspid aortic valve; segregation studies for the remaining four individuals were either not completed or non-informative (Kerstjens-Frederikse et al., 2016). R912W was observed in approximately 0.3% of alleles from individuals of European (Non-Finnish) ancestry and 0.2% of alleles from individuals of both Latino and European (Finnish) ancestry in the Exome Aggregation Consortium, indicating it may be a rare benign variant in these populations (Lek et al., 2016). Furthermore, this substitution occurs at a position that is not conserved across species. Nevertheless, R912W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 27, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Blueprint Genetics	Jan 29, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 08, 2019	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;C4014970:Adams-Oliver syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

NOTCH1 NM_017617.5 exon 17 p.Arg912Trp (c.2734C>T): This variant has been reported in the literature in one individual with an aortic aneurysm and in five individuals with nonsyndromic congenital heart disease (bicuspid aortic valve, coarctation of the aorta, aortic valve stenosis) (Ziganshin 2015 PMID:26188975, Kerstijens-Frederikse 2016 PMID:26820064). However, this variant is also present in 0.2% (317/119414) of European alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/9-139405111-G-A). This variant is present in ClinVar (Variation ID:134921). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Aortic valve disease 1

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Adams-Oliver syndrome 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Benign

0.16

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

0.96

MutationTaster

Benign

0.76

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.40

Sift

Uncertain

0.017

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.46

MVP

0.74

MPC

1.0

ClinPred

0.032

GERP RS

2.9

Varity_R

0.14

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