19-15192130-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_000435.3(NOTCH3):c.509A>G(p.His170Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00289 in 1,612,974 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 11 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 7.11

Variant links:

Genes affected

NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 3 uncertain in NM_000435.3

BP4

Computational evidence support a benign effect (MetaRNN=0.014457643).

BP6

Variant 19-15192130-T-C is Benign according to our data. Variant chr19-15192130-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 328418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15192130-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.509A>G	p.His170Arg	missense_variant	4/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.509A>G	p.His170Arg	missense_variant	4/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.509A>G	p.His170Arg	missense_variant	4/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.506A>G	p.His169Arg	missense_variant	4/23	5

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

244

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00257

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00184

AC:

457

AN:

248134

Hom.:

AF XY:

0.00212

AC XY:

286

AN XY:

135036

show subpopulations

Gnomad AFR exome

AF:

0.000629

Gnomad AMR exome

AF:

0.000754

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00461

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.00245

Gnomad OTH exome

AF:

0.000824

GnomAD4 exome

AF:

0.00303

AC:

4422

AN:

1460714

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

2244

AN XY:

726688

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00424

Gnomad4 FIN exome

AF:

0.0000956

Gnomad4 NFE exome

AF:

0.00339

Gnomad4 OTH exome

AF:

0.00374

GnomAD4 genome

AF:

0.00160

AC:

244

AN:

152260

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00257

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00156

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00188

AC:

228

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00262

EpiControl

AF:

0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NOTCH3: PP2, BS1, BS2 -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 5 individuals with CADASIL. Also identified in 3 individuals with ischemic strokes, but the frequency was not different in controls. No segregation data available. No new publications since 2013. MAF 0.4%, too high to be consistent for a pathogenic role in AD highly penetrant disease. -

NOTCH3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;D

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.1

D;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.0060

D;.

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.97

D;.

Vest4

0.82

MVP

0.94

MPC

0.93

ClinPred

0.049

GERP RS

4.9

Varity_R

0.44

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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