rs10423702

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000435.3(NOTCH3):c.1192+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,613,816 control chromosomes in the GnomAD database, including 615,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 57808 hom., cov: 33)

Exomes 𝑓: 0.87 ( 558122 hom. )

Consequence

NOTCH3
NM_000435.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.58

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
lateral meningocele syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
infantile myofibromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myofibromatosis, infantile, 2
Inheritance: AD Classification: LIMITED Submitted by: G2P
pulmonary arterial hypertension
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 19-15189258-T-C is Benign according to our data. Variant chr19-15189258-T-C is described in ClinVar as Benign. ClinVar VariationId is 256118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.1192+15A>G		intron_variant	Intron 7 of 32	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 link	c.1192+15A>G		intron_variant	Intron 7 of 31		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.1192+15A>G		intron_variant	Intron 7 of 32	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1 link	c.1189+15A>G		intron_variant	Intron 7 of 22	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes

AF:

0.870

AC:

132361

AN:

152124

Hom.:

57770

Cov.:

show subpopulations

Gnomad AFR

AF:

0.907

Gnomad AMI

AF:

0.866

Gnomad AMR

AF:

0.762

Gnomad ASJ

AF:

0.877

Gnomad EAS

AF:

0.865

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.862

Gnomad MID

AF:

0.870

Gnomad NFE

AF:

0.877

Gnomad OTH

AF:

0.849

GnomAD2 exomes

AF:

0.848

AC:

212880

AN:

251110

AF XY:

0.850

show subpopulations

Gnomad AFR exome

AF:

0.909

Gnomad AMR exome

AF:

0.702

Gnomad ASJ exome

AF:

0.870

Gnomad EAS exome

AF:

0.863

Gnomad FIN exome

AF:

0.866

Gnomad NFE exome

AF:

0.879

Gnomad OTH exome

AF:

0.845

GnomAD4 exome

AF:

0.873

AC:

1275900

AN:

1461574

Hom.:

558122

Cov.:

AF XY:

0.872

AC XY:

633882

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.908

AC:

30389

AN:

33480

American (AMR)

AF:

0.707

AC:

31634

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.870

AC:

22749

AN:

26136

East Asian (EAS)

AF:

0.880

AC:

34944

AN:

39700

South Asian (SAS)

AF:

0.838

AC:

72243

AN:

86258

European-Finnish (FIN)

AF:

0.866

AC:

45993

AN:

53116

Middle Eastern (MID)

AF:

0.822

AC:

4740

AN:

5768

European-Non Finnish (NFE)

AF:

0.882

AC:

981250

AN:

1112002

Other (OTH)

AF:

0.860

AC:

51958

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

11007

22014

33020

44027

55034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21340

42680

64020

85360

106700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.870

AC:

132450

AN:

152242

Hom.:

57808

Cov.:

AF XY:

0.867

AC XY:

64497

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.907

AC:

37712

AN:

41574

American (AMR)

AF:

0.762

AC:

11644

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.877

AC:

3044

AN:

3472

East Asian (EAS)

AF:

0.866

AC:

4468

AN:

5162

South Asian (SAS)

AF:

0.830

AC:

4005

AN:

4824

European-Finnish (FIN)

AF:

0.862

AC:

9133

AN:

10590

Middle Eastern (MID)

AF:

0.861

AC:

253

AN:

294

European-Non Finnish (NFE)

AF:

0.877

AC:

59613

AN:

68012

Other (OTH)

AF:

0.846

AC:

1788

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

887

1775

2662

3550

4437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.870

Hom.:

51148

Bravo

AF:

0.865

Asia WGS

AF:

0.835

AC:

2901

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19006080)

Jan 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lateral meningocele syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.30

(source)

DANN

Benign

0.24

PhyloP100

-3.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over