rs61751542

Positions:

Variant summary

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

The NM_017617.5(NOTCH1):c.4129C>T(p.Pro1377Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,587,054 control chromosomes in the GnomAD database, including 441 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1377L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 38 hom., cov: 33)

Exomes 𝑓: 0.020 ( 403 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:17O:1

Conservation

PhyloP100: -0.0870

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=0.0028090775).

BP6

Variant 9-136505767-G-A is Benign according to our data. Variant chr9-136505767-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136505767-G-A is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0615 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.4129C>T	p.Pro1377Ser	missense_variant	25/34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3 linkuse as main transcript	c.3406C>T	p.Pro1136Ser	missense_variant	22/31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.4129C>T	p.Pro1377Ser	missense_variant	25/34		NM_017617.5	ENSP00000498587	P1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2278

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00388

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.0882

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0208

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0170

AC:

3746

AN:

220252

Hom.:

AF XY:

0.0175

AC XY:

2119

AN XY:

121430

show subpopulations

Gnomad AFR exome

AF:

0.00398

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0845

Gnomad EAS exome

AF:

0.0000589

Gnomad SAS exome

AF:

0.00747

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0292

GnomAD4 exome

AF:

0.0198

AC:

28349

AN:

1434728

Hom.:

403

Cov.:

AF XY:

0.0198

AC XY:

14055

AN XY:

710784

show subpopulations

Gnomad4 AFR exome

AF:

0.00403

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0855

Gnomad4 EAS exome

AF:

0.0000764

Gnomad4 SAS exome

AF:

0.00779

Gnomad4 FIN exome

AF:

0.00399

Gnomad4 NFE exome

AF:

0.0208

Gnomad4 OTH exome

AF:

0.0238

GnomAD4 genome

AF:

0.0149

AC:

2276

AN:

152326

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1086

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00387

Gnomad4 AMR

AF:

0.0153

Gnomad4 ASJ

AF:

0.0882

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00724

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.0208

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0258

Hom.:

Bravo

AF:

0.0169

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00302

AC:

ESP6500EA

AF:

0.0234

AC:

186

ExAC

AF:

0.0158

AC:

1874

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2016	- -
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	Jul 21, 2023	- -
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+	-	- -
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	Eurofins Ntd Llc (ga)	Aug 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NOTCH1: BP4, BS1, BS2 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 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. -

Adams-Oliver syndrome 5

Benign:2

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

Myeloproliferative neoplasm, unclassifiable

Pathogenic:1

Pathogenic, flagged submission

clinical testing

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Aug 25, 2022

- -

Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 07, 2021

- -

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

0.059

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.79

DANN

Benign

0.84

DEOGEN2

Benign

0.23

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.33

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.16

REVEL

Uncertain

0.32

Sift

Benign

0.59

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.099

MPC

0.38

ClinPred

0.0015

GERP RS

-2.5

Varity_R

0.042

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