rs2229974

Variant summary

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

The NM_017617.5(NOTCH1):c.6555C>T(p.Asp2185=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,612,574 control chromosomes in the GnomAD database, including 272,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 27352 hom., cov: 34)

Exomes 𝑓: 0.57 ( 244678 hom. )

Consequence

NOTCH1
NM_017617.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.259

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=-0.6).

BP6

Variant 9-136497184-G-A is Benign according to our data. Variant chr9-136497184-G-A is described in ClinVar as [Benign]. Clinvar id is 286141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136497184-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.259 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH1	NM_017617.5 linkuse as main transcript	c.6555C>T	p.Asp2185=	synonymous_variant	34/34	ENST00000651671.1
NOTCH1	XM_011518717.3 linkuse as main transcript	c.5832C>T	p.Asp1944=	synonymous_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.6555C>T	p.Asp2185=	synonymous_variant	34/34		NM_017617.5	P1

Frequencies

GnomAD3 genomes

AF:

0.594

AC:

90363

AN:

152036

Hom.:

27331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.648

Gnomad ASJ

AF:

0.532

Gnomad EAS

AF:

0.939

Gnomad SAS

AF:

0.686

Gnomad FIN

AF:

0.512

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.579

GnomAD3 exomes

AF:

0.622

AC:

154009

AN:

247630

Hom.:

49771

AF XY:

0.619

AC XY:

83492

AN XY:

134958

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.725

Gnomad ASJ exome

AF:

0.539

Gnomad EAS exome

AF:

0.950

Gnomad SAS exome

AF:

0.677

Gnomad FIN exome

AF:

0.515

Gnomad NFE exome

AF:

0.551

Gnomad OTH exome

AF:

0.587

GnomAD4 exome

AF:

0.573

AC:

837301

AN:

1460420

Hom.:

244678

Cov.:

AF XY:

0.576

AC XY:

418836

AN XY:

726538

show subpopulations

Gnomad4 AFR exome

AF:

0.621

Gnomad4 AMR exome

AF:

0.714

Gnomad4 ASJ exome

AF:

0.531

Gnomad4 EAS exome

AF:

0.909

Gnomad4 SAS exome

AF:

0.680

Gnomad4 FIN exome

AF:

0.520

Gnomad4 NFE exome

AF:

0.549

Gnomad4 OTH exome

AF:

0.589

GnomAD4 genome

AF:

0.594

AC:

90415

AN:

152154

Hom.:

27352

Cov.:

AF XY:

0.600

AC XY:

44643

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.620

Gnomad4 AMR

AF:

0.649

Gnomad4 ASJ

AF:

0.532

Gnomad4 EAS

AF:

0.939

Gnomad4 SAS

AF:

0.686

Gnomad4 FIN

AF:

0.512

Gnomad4 NFE

AF:

0.552

Gnomad4 OTH

AF:

0.581

Alfa

AF:

0.568

Hom.:

31052

Bravo

AF:

0.607

Asia WGS

AF:

0.786

AC:

2732

AN:

3478

EpiCase

AF:

0.566

EpiControl

AF:

0.566

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
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)	Feb 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 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	Clinical Genetics, Academic Medical Center	-	- -

Aortic valve disease 1

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Adams-Oliver syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

Cadd

Benign

0.94

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