rs11574911

Positions:

Variant summary

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

The NM_017617.5(NOTCH1):c.7233A>G(p.Pro2411Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,602,606 control chromosomes in the GnomAD database, including 334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 176 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 158 hom. )

Consequence

NOTCH1
NM_017617.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.610

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=-0.91).

BP6

Variant 9-136496506-T-C is Benign according to our data. Variant chr9-136496506-T-C is described in ClinVar as [Benign]. Clinvar id is 285559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136496506-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.7233A>G	p.Pro2411Pro	synonymous_variant	34/34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.6510A>G	p.Pro2170Pro	synonymous_variant	31/31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.7233A>G	p.Pro2411Pro	synonymous_variant	34/34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4037

AN:

152200

Hom.:

172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0884

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.00758

AC:

1793

AN:

236620

Hom.:

AF XY:

0.00577

AC XY:

749

AN XY:

129914

show subpopulations

Gnomad AFR exome

AF:

0.0913

Gnomad AMR exome

AF:

0.00608

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.0000726

Gnomad NFE exome

AF:

0.000803

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00335

AC:

4856

AN:

1450288

Hom.:

158

Cov.:

AF XY:

0.00295

AC XY:

2128

AN XY:

721844

show subpopulations

Gnomad4 AFR exome

AF:

0.0912

Gnomad4 AMR exome

AF:

0.00707

Gnomad4 ASJ exome

AF:

0.0124

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.000237

Gnomad4 NFE exome

AF:

0.000555

Gnomad4 OTH exome

AF:

0.00778

GnomAD4 genome

AF:

0.0266

AC:

4059

AN:

152318

Hom.:

176

Cov.:

AF XY:

0.0259

AC XY:

1929

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0887

Gnomad4 AMR

AF:

0.0147

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.0306

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 02, 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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 15, 2016	- -

not provided

Benign:2

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 08, 2023	- -

Adams-Oliver syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

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

-0.91

CADD

Benign

0.082

DANN

Benign

0.32

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