rs3812596

Positions:

chr9-136497091-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017617.5(NOTCH1):c.6648G>A(p.Pro2216=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,609,458 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 153 hom. )

Consequence

NOTCH1
NM_017617.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.70

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 9-136497091-C-T is Benign according to our data. Variant chr9-136497091-C-T is described in ClinVar as [Benign]. Clinvar id is 287652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136497091-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.7 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0515 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.6648G>A	p.Pro2216=	synonymous_variant	34/34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3 linkuse as main transcript	c.5925G>A	p.Pro1975=	synonymous_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.6648G>A	p.Pro2216=	synonymous_variant	34/34		NM_017617.5	ENSP00000498587	P1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1601

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0304

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0567

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00719

GnomAD3 exomes

AF:

0.0121

AC:

2962

AN:

244490

Hom.:

AF XY:

0.0104

AC XY:

1390

AN XY:

133840

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.0389

Gnomad ASJ exome

AF:

0.000406

Gnomad EAS exome

AF:

0.0541

Gnomad SAS exome

AF:

0.00367

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.00436

AC:

6349

AN:

1457174

Hom.:

153

Cov.:

AF XY:

0.00430

AC XY:

3117

AN XY:

724348

show subpopulations

Gnomad4 AFR exome

AF:

0.0160

Gnomad4 AMR exome

AF:

0.0386

Gnomad4 ASJ exome

AF:

0.000307

Gnomad4 EAS exome

AF:

0.0638

Gnomad4 SAS exome

AF:

0.00420

Gnomad4 FIN exome

AF:

0.00177

Gnomad4 NFE exome

AF:

0.000725

Gnomad4 OTH exome

AF:

0.00474

GnomAD4 genome

AF:

0.0106

AC:

1613

AN:

152284

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

862

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0170

Gnomad4 AMR

AF:

0.0304

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0568

Gnomad4 SAS

AF:

0.00664

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.00652

Hom.:

Bravo

AF:

0.0139

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2017	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, 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, Amsterdam University Medical Center	-	- -

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	Jan 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 22, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 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	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.26

DANN

Benign

0.84

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