9-136515524-C-T

Position:

chr9-136515524-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_017617.5(NOTCH1):c.1862G>A(p.Arg621His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,611,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R621R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 2.47

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 Benign. Variant got -13 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=0.12021786).

BP6

Variant 9-136515524-C-T is Benign according to our data. Variant chr9-136515524-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136515524-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NOTCH1	NM_017617.5 linkuse as main transcript	c.1862G>A	p.Arg621His	missense_variant	11/34	ENST00000651671.1	NP_060087.3
LOC124902310	XR_007061865.1 linkuse as main transcript	n.507+5545C>T		intron_variant, non_coding_transcript_variant
NOTCH1	XM_011518717.3 linkuse as main transcript	c.1139G>A	p.Arg380His	missense_variant	8/31		XP_011517019.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 linkuse as main transcript	c.1862G>A	p.Arg621His	missense_variant	11/34		NM_017617.5	ENSP00000498587	P1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00104

AC:

254

AN:

245308

Hom.:

AF XY:

0.00111

AC XY:

149

AN XY:

133912

show subpopulations

Gnomad AFR exome

AF:

0.000396

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00191

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000636

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.00120

AC:

1748

AN:

1459622

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

870

AN XY:

726184

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00169

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.000777

Gnomad4 NFE exome

AF:

0.00134

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.000906

AC:

138

AN:

152304

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00172

Hom.:

Bravo

AF:

0.000929

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000929

AC:

ESP6500EA

AF:

0.00141

AC:

ExAC

AF:

0.00115

AC:

139

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NOTCH1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 02, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	This variant is associated with the following publications: (PMID: 24728327, 28387797) -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 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. -

Adams-Oliver syndrome 5

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Aortic valve disease 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

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

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

0.32

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.55

Sift

Benign

0.14

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.60

MVP

0.78

MPC

1.3

ClinPred

0.043

GERP RS

5.2

Varity_R

0.15

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